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Zoe Brown
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This 49 page Class Notes was uploaded by Zoe Brown on Friday October 23, 2015. The Class Notes belongs to 149 197 at University of Iowa taught by Staff in Fall. Since its upload, it has received 20 views. For similar materials see /class/228010/149-197-university-of-iowa in American Indian Studies (AIS), History (HIST), Holistic Health (HH) at University of Iowa.

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Date Created: 10/23/15
Critim Reviewfo in Immumagy 233 149197 2003 AntigenSpecific BLymphocyte Activation Gail A Bishop7r2r4r5r Sokol A Haxhinasto Laura L Stunz amp Bruce S Hostager3 Departments of 1Microbiology 2Internal Medicine and 3Pediatrics and the AGraduate Program in Immunology The University of Iowa and the 5VAMC Iowa City IA 52242 3 Address all correspondence to Gail Bishop PhD Department ofMicrobioIogy 3570 Bowen Science Building Iowa City IA 52242Te1 3193354945 Email gailrbishopuiowaedu Referee D Oklahoma Clly OK 73104 r K Mark Coggeshall Oklahoma Medical Research Foundauon Immunoblology amp Cancer 825 NE 13m SL ABSTRACT B lymphocytes comprise a major component of the adaptive mammalian immune system having the exclusive ability to produce and secrete immunoglobulins lg ofvarious forms isotypes This property alone renders Bicell activation critical to immunity but the fully activated B cell also functions in antigen presentation and the production ofa variety of cytokines and chemokines There are many signals that must be coordinated to achieve and properly regulate antigenrspeci c Bil This review seeks to sum marize these components and to high phocyte activation and the development ofhumoral memo light recent advances in each area that contribute to a greater understanding of the complex processes involved in Bicell activation KEYWORDS receptors signal transduction immunoglobulin TNFR family memory I INTRODUCTION The study of mammalian immunity over many decades has clearly shown that an effective immune system requires the normal functioning of all types of hematopoietic cells Protection from pathogens requires that both the innate and adaptive arms of immunity function well and in concert One ofthe major components of adaptive immunity is the umoral or antibodyemediated immune responsei the exclusive purview of the B lymphocyte A va riety of immune system cells produce lymphokines and chemokines but only B lymphocytes make immunoglobulins lg and a lack of antibodies even of certain isotypes leads to profound comproe mises in immunity1 4 Although lg production is a unique Becell function effective activation of B lymphocytes is important to normal immune function in additional ways Dendritic cells are the most effective antigenepresenting cells APC for most activation events of naive T lymphocytes5 but B lymphocytes can serve as important APC in 104084010335500 2003 by Begell House Inc certain situations and play roles in the stimulation of normal immunity autoimmunity and toleri ance5 23 it is thus not surprising that a complete lack of B cells or a failure in Becell activation pathways also leads to defects in Tecell activae tion2 7 so while it has long been recognized that adaptive humoral immunity requires normal cell mediated immune function it is now becoming appreciated that the converse is also true ere are two major avenues for Belymphocyte activation activation that occurs in the context of cognate interaction with an activated T lymphocyte whose receptor recognizes antigen presented by the B cell or activation by Teindependentyl Tl antigens The latter can bind either all Becell antigen receptors regardless ofspecificity Tl type 1 or bind to other antigen nonspecific activation receptors expressed by all B cells Tl type 2 Because each type of Becell activation is itself a major topic in this review we will con ne ourselves to Tedependent antigene speci c Becell activation The reader is referred to other excellent articles 149 to begin to explore the topic of Teindependent Becell activation 29 Tedependent Becell activation is initiated by binding of antigen to the combining site of the Becell antigen receptor BCR the membrane form of Ig This binding has two important consequences First it initiates internalization of the antigen into specialized intracytoplasmic come partments where antigen is processed and its peptide fragments loaded onto MHC class H molecules for membrane presentation to T cells30 Second engagement of the BCR by antigen stimulates formation of a membrane signaling complex consisting of both the BCR and a va riety ofcoereceptors which regulates Becell actie vation in both positive and negative ways Upon successful antigen presentation to an activated lemphocyte B cells receive many additional regulatory signals These include signals delive ered via contactemediated receptoriligand inter actions as well as receipt of signals delivered by soluble chemokines and lymphokines The cule mination and interaction of all these various sig naling pathways determines the ultimate out come of the encounter with antigeniclonal expansion and differentiation plasma cell formae tion or longeterm survival as a memory B cell in a germinal center These signals also regulate the development of Becell tolerance Each of these signals and steps in activation are discussed in turn in the following review It is clear that much is now known about Becell activation including the identity of many of the receptors involved their signaling mechanisms and the functional consequences of signal delivery But it is equally clear that much remains to be understood Pref viously unidentified receptors involved in Becell activation are being discovered at a rapid pace How each plays its roles in the process and especially how the B cell integrates all this infor mation from its environment are questions that await further elucidation II THE BCR COMPLEX The Becell antigen receptor BCR is absolutely required during Becell development and differ entiation The BCR plays an essential role early in Becell development in many processes include 150 ing allelic exclusion and gene recombination at the lightechain loci negative and positive selece tion and aner and receptor editing 32 Tare geted disruption ofthe BCR complex has revealed its necessary role in selection into the peripheral Becell population maintenance of the Becell repe ertoire response to antigen and selection into the memory Becell pool 32 Because ofthe important physiological role of B lymphocytes in the ime mune system extensive research is devoted to J J39 I I 1 the lllUlCLuldJ C and sig naling pathways that regulate BCRemediated 13 cell activation The individual events and mole ecules involved are described below and summarized in schematic form in Figure 1 The BCR is a multimeric protein complex in which the antigen binding and the signal transduce tion subunits are distinct The antigen recognition binding module is the membrane Tg ng which is a tetrameric complex of immunoglobulin heavy TgH and light TgL chains The signale transmitting component consists ongeoc CD79a and Tge CD79b which form a disulfidee bonded heterodimer33 The critical role of the membrane form of the 1 chain is evident in mice lacking this gene which results in blockade at the proeBecell stage and loss of H chain allelic exclusion34 35 Elegant studies by Lam et al using CreJnxPemediated inducible gene targeting demonstrated that BCR expression is required for the persistence of mae ture B cells in the peripheral immune system and its deletion leads to elimination via apoptosis of receptorless B cells36 Association of 1 chain with its signaling modules Tgeoc and Tge is essential for allelic exclusion and developmental progress to the preeBecell stage evident in mice transgenic for a mutant 1 chain that is not able to associate with endogenous Tgeoc and Tge 37 The contribution of Tgeoc and Tge in Becell development and BCR signaling has been as sessed in a systematic manner by generations of mice either deficient in or containing mutant versions ofeach ofthe components Recent stud ies have revealed distinct and complementary roles for Tgeoc and Tge Reichlin et al compared Becell development and BCR signaling among mice carrying a deletion in the cytoplasmic domain of Tgeoc IgiocAC or Tge Tge BAC38 Whereas both mouse mutants show a dramatic decrease in the Critim Reviewxw in ImmumUgy 39 larl ll mil mlll l FIGURE 1 Antigen recognition by the BCR leads to activation of several protein tyrosine kinases including Lyn Syk and Btkr Tyrosine phosphorylation of adaptor proteins such as BLNK links BCR engagemen t to downstream signaling pathways regulated by Plr3K PLCryZ PKC and Rasr Cell surface correceptors activate additional signal Dr Dquot LLquot UC I I gr CD22 and CD32 The integration of multiple signaling pathways culminates in activation of transcription factors and gene regulation as detailed in the text number of splenic B cells Becell development is abruptly terminated at the immature stage in lg BAC mice versus lgeaAC mice in which B cells are lost throughout developmenti Additionally B cells from lgeBAC mice display normal cal cium Ca2 mobilization upon BCR engage ment3g whereas this response is enhanced and prolonged in lgeaAC mice and associated with strong protein tyrosine phosphorylation suggeste ing a negative role for lgeaw40 Further analysis of lgeaAC mice showed that immature B cells are unexpectedly activated thereby mimicking self reactive B cells which might explain why they are eliminated39 Therefore lgea and lgeB play differential roles depending on the differentiae tion stage of B ce s The signaling functions of lgea and lgeB de pend primarily on the immunoreceptor tyrosine based activation motif ITAM found in the cytoe plasmic CY domain 42 Each ITAM has the Volume 23 Number 3 amino acid sequence DEX7DEXXYX1dLX7YUIL The two tyrosine residues serve as protein tyrosine kinase PTK substrates and once phosphorye lated function as docking sites for downstream signaling molecules 1 BCR engagement leads to lgeo ITAM phosphorylation by Lyn a Src kinase family memberi The crucial role of ITAM tyrosine phosphorylation is apparent in mice ex pressing lga in which the two tyrosines in the ITAM motif were replaced by phenylalanines lg OFFFF These mice show defects in develop ment of B1 and marginal zone B cells and in response to Tecelledependent TD antigensi Confirming a negative role of lgeavfg40 these mutants displayed exaggerated Ca2 ux lntereste ingly the phosphorylation of Lyn and Syk is not completely abolished but is delayed and reduced suggesting a role for the nonelTAM tyrosines in BCResignalingi Recent studies have demonstrated a role for the nonelTAM tyrosines Y176 and Y204 in the Igioc CY tail in linking Syk activation to Becell linker protein BLNKydependent path ways 45 Despite similarities between the ITAM motifs in Igioc and Ige there seem to be differences in magnitude of phosphorylation which could account for the differences in PTKs associated with each of the receptors4547 Upon BCR engagement Syk has been shown to bind primarily to Ige rather than Tgeoc48 whereas BLNK interacts primarily with Igioc For a more extensive coverage of the role of Igioc and Tge in Becell activation refer to recent excellent reviews 49 A Protein Tyrosine Kinases The transmission ofsignals from the BCR to the nucleus relies on the activation ofprotein tyrosine kinases PTKs which occurs immediately after BCR engagement Extensive work in this area has shown that the BCR activates three distinct types of PTKs the Src Syk and Tec family kinases This section will focus on representatives from each family Lyn is a member ofthe Src family oftyrosine kinases which is expressed in various cell types50 It was initially identified as a homologous gene to other in family members51 and it exists in two isoforms p561y and p531y 52 Structurally Lyn consists of SH2 and SH3 domains enabling it to interact with other proteins by recognizing phosphotyrosineecontaining or prolineerich ref gions respectively53 In addition Lyn has a catae lytickinase domain necessary for regulation of other proteins via tyrosine phosphorylation Src kinases contain two primary regulatory tyrosine residues whose phosphorylation can lead to en hancement Tyr7397 within the kinase domain or inhibition Tyr7508 within the Ceterminal tail of activity5354 BCR engagement leads to rapid tyrosine phosphorylation and activation of Lyn 5 5 which leads to further phosphorylation of the ITAM of Igioc thereby creating docking sites for SH2 domainecontaining downstream signal ing molecules57 Activation of Src family kinases such as Lyn is counterbalanced by Csk a cytoe plasmic PTK that exerts its regulatory effect via phosphorylation of the Ceterminal inhibitory tyrosine residue58 59 Mice deficient for Csk die early in development and display enhanced Lyn 152 kinase activity60m This is also evident in Cske deficient B cells52 supporting a critical negative role for Csk in Lyn activation Mice de cient for Lyn have decreased numbers of peripheral B cells and are defective in their responses to TD and TI antigens63 In addition to the positive roles that Lyn plays in BCResignaling initiation the knockout mice suggest negative roles for Lyn in B lymphocytes B cells from Lyn have increased Ca2 flux spontaneous hyperactivity mice in the absence of antigen increased mitogeneactie vated protein kinase MAPK activation and inf creased proliferative response upon BCR engagei ment6 mice are also characterized by splenomegaly and production of autoantibodies supporting a critical inhibitory role for Lyn in BCR signaling The negative contribution of Lyn is believed to be mediated via phosphorylation of the immunoreceptor tyrosineebased inhibitory motif ITIM found on CD22 see discussion of CD22 below These data support a multipurpose role for Lyn in B lymphocytes Phosphorylation of tyrosines in the ITAM leads to recruitment of Syk a member of the Syk PT K family that serves a crucial role in transduce tion of signals emanating from the BCR Syk consists of two SH2 domains separated by a unique linker region and a Ceterminal catalytic domain66 The critical role of Syk in BCR signale ing is evident in Syk mice which have a block in Becell development at the proeB to preeBecell transition 68 These mice are also deficient in mature B cells supporting a role for Syk in their maintenance BCR engagement results in ref cruitment and association of Syk with the BCR complex69 The presence and phosphorylation of both conserved tyrosines within ITAM motifs is necessary for efficient recruitment of Syk via its SH2 domains70 Recent work in Drampb a S2 Schneider cells has challenged the necessity for both ITAM tyrosines to be phosphorylated for Syk recruitment and suggests that Syk recruite ment is independent of Lyn71 However this needs confirmation in B cells BCR recruitment of Syk leads to increased autophosphorylation at Y518Y519 which ultimately enhances Syk catae lytic activity70 Syk is itself tyrosine phosphorye lated on multiple residues772 73 each of which might play different roles in Syk association with and disassociation from the BCR74 or activation of Critim Reviewxw in ImmumUgy downstream signaling pathways7475 Tyrosine phosphorylation enables Syk to phosphorylate downstream adaptor proteins such as BLNK which then serves as a docking site for phosphoe lipase CW2 PLCWZ and facilitates its recruite ment to the plasma membrane nce in the plasma membrane PLCWZ is phosphorylated and activated by Syk and Btk76 The Tec family of PTKs predominantly Bruton s tyrosine kinase Btk also plays a posi tive role in BCR signaling77 Btk contains an Neterminal pleckstrin homology domain PH a prolineerichTec homology TH region SH3 and SHZ domains and aceterminal catalytic domain which allow interaction of Btk with a variety of signaling molecules78 impacting multiple signal ing pathways Mutations in each of the domains have been reported to cause Xelinked agammae globulinemia XLA in humans7931 Interestingly Btk is the only protein known where mutations in the PH domain cause a disease The PH domain is important for membrane localization othk via interactions with phosphatidylinositol 345 triphosphate PIE82 When recruited to the plasma membrane Btk is brought in proximity to the BLNK7PLC42 complex via the 5H27domain which binds to tyrosine phosphorylated BLNK This recruitment enables Btk to induce tyrosine phosphorylation ofPLC42 and initiates produce tion ofinositoletrisephosphate 1P3 and mobilizae tion of Cali 83 Mutations in the PH domain are detrimental to Btk function by interfering with Btk binding to PIP This is evident in humans with XLASO 81 and in mice with X chromosomeelinked immunoe deficiency XID84 85 XLA patients have reduced numbers of BCRepositive B cells because of a developmental blockade at the preeBecell stage and low levels oflg in the serum and are therefore susceptible to bacterial infections86 Interestingly Btk mice display a more similar phenotype to XlD mice than XLA patients sug gesting a differential role for Btk among different species 88 A point mutation in the PH domain E41K leads to increased membrane association tyrosine phosphorylation and more importantly transforming activity89 suggesting a role for Btk in oncogenesis and the necessity of a negative regulatory mechanism Recently protein kinase beta PKC and a novel inhibitor of Btk lBtk Volume 23 Number 3 were shown to negatively regulate Btk activity9 91 PKCBwas shown to exert its inhibitory effects via serineephosphorylation within the TH domain affecting membrane translocation90 whereas lBtk binds to the PH domain and impedes the kinase activity Ca mobilization and nuclear factoreKB NFeKB activation91 These data point to mule tiple regulatory mechanisms that ensure approprie ate threshold and specificity of Btkemediated events The central role that Btk plays in B lymphoe cytes is underscored by the similar XlD phenoe type observed in mice lacking other molecules that interact with or influence Btk activation such as the p850c subunit ofphosphatidylinositole 3 kinase PI3K49 92 BLNKRW4 PKCB PLC42 and VavlVav29798 All these mice show defects in Ca regulation emphasizing the interdependence among these proteins B Adaptor Proteins Activated Lyn Syk Btk and other PTKs phose phorylate additional signaling molecules which leads to production ofvarious second messengers and initiation of multiple intermediary signaling pathways The link between PTKs and downe stream signaling molecules is mediated via adape tor proteins which do not possess inherent enzye matic activity but serve as scaffolds by enabling interactions among various molecules via differ ent domains Adaptor proteins play an important role in subcellular localization conformational rearrangement and interaction among effector molecules enabling a tightly and accurately regue lated signaling network This section will focus on BLNK Vav and Cbl BLNK was originally identified as a 70kDa tyrosine phosphoprotein preferentially expressed in B lymphocytes 100 Fu et al demonstrated that BCR engagement leads to Sykeinduced tyroe sine phosphorylation ofBLNK creating docking sites for downstream effector molecules101 By bringing multiple effector molecules in close proxe imity to each other ie Btk PLC7y283 BLNK enables interactions among them as well as the necessary crossetalk among various signaling path ways Using gene targeting to generate BLNKe deficient B cells lshiai et al show that BLNK is necessary for the recruitment of PLC42 to the plasma membrane where it can exert its effects on its substrate phosphatidylinositol 457biphosphate Pl 457P2 and induce Ca mobilization In ad dition the Rac1eNK pathway is dependent upon BLNK expression102 The crucial role of BLNK in Becell develop ment is evident in mice lacking BLNK in which Becell development is blocked at the preeB and immatureeBecell stages9394 There is a dramatic decrease in peripheral B cells in the spleen and lymph node and a lack of B71 cells Functional analysis of BLNKrdC CiCHt B cells revealed a role for BLNK in the proliferative responses to BCR CD40 and mitogen since both these and Ca2 mobilization are defective when compared to wildetype cells However the Ca2 response is not completely abolished pointing to other BLNKe independent pathways regulating Ca2 mobilizae tion9394 Con rming the central role ofBLNK in Becell signaling these mice also show defects in lgM and lgG3 responses to T1 and TD antie gens93 Recent examination of BLNK mice 97 14 weeks of age demonstrates the presence of solid tumors consisting exclusively ofpreeB cells and splenomegaly pointing to a novel role for BLNK as a tumor suppressor103 One of the molecules that interacts with BLNK is the guanineenucleotide exchange factor Vav reviewed in Ref 104 Structurally Vav proteins Vave1 Vav72 and Vave3 contain several prof teineinteraction domains including a calponine homology domain a diffuse Becell lymphomae homology domain a PH domain a Zincefinger domain a prolineerich region and two SH3 doe mains separated by an SH2 domain104 The pres ence of multiple domains allows Vav to interact with various signaling molecules Yeastetwo hyi brid experiments as well as in Win studies using antieBCR stimulated cells show that Vav interacts with Syk this interaction is dependent on the activity ofSyk and the SH2 domain ofVav Vav activation also leads to activation of the Rhoe family GTPases106 which serve as molecular switches for downstream signaling molecules inf cluding cejun kinase INK and p3807 CD19 is also able to activate and synergize with the BCR in Vav tyrosine phosphorylation and consequently Ca2 mobilization and INK activation108 see CD19 discussion below 154 Genetic studies have been used to dissect the role of Vav proteins in Belymphocyte activation Mice deficient for Vave1109 110 or Vav7297 98 dis play normal Becell development in the bone marrow partial decrease in Ca2mobilization and BCReinduced proliferation suggesting a reduni dant role for these molecules Vav1 Vav2 mice display a more profound defect evident in the complete abrogation of Ca2mobilization a drae matic decrease in absolute number of splenic B cells and impaired Becell maturation97 98 Howe ever additional data suggest that Vave1 and Van have distinct noneoverlapping roles in B lymphoi cytes Vav1 but not Vav2 mice lack B1 cells whereas only Vav23939 mice show defects in ref sponse to T172 and TD antigens isotype switche ing and germinal center formation98 The phenoi type of Vav1 Vav2 mice resembles the XlD phenotype associated with other components of the signalosome see above discussion underi scoring the crucial role of a properly assembled signaling complex The cCbl protoeoncogene was initially idene tified in mice infected with a retrovirus that caused pref and proeB lymphomas111 The comparison of vecbl and cecbl sheds light on important structural requirements for tumorigenesis as well as on the function obel12 Cbl family are ubiquitously expressed113 114and are notable for the RING domain which endows Cbl proteins with ubiquitin ligase properties Ene gagement of the BCR leads to Lynedependent tyrosine phosphorylation ofcecbl16 Phosphorylae tion of cecbl creates docking sites for other signali ing proteins such as the p85 subunit of P1731017 and Btk118 thereby affecting their function Using Cbl DT40 B cells Yasuda et al show a negative role for Cbl in regulating the PLC42 pathway by interfering with the association of BLNK with PLCWZ19 Cbledeficient B cells display hypere phosphorylation of PLCWZ perhaps because of increased association with BLNK and enhanced IF and Ca2 responses119 Interestingly another member of the Cbl family Cbleb plays a positive role in BCR signaling by enhancing the interaction of PLC42 with Btk and BLNK resulting in a 120 e members ofthe sustained Ca2 response Analysis obelideficient mice has revealed a role for Cbleb in regulating the signaling threshe old of antigen receptors and preventing develope Critim Reviewxw in ImmumUgy ment of autoimmunity121122 Cbleb mice are characterized by multiple organ in ltration of B and T cells Whereas loss obeleb does not affect development and selection ofB cells the cells are hypereresponsive to antieBCR and anti7CD40 signals supporting a negative role for Cblib in these pathways121 Current data raise interesting questions about whether Cbl proteins play posie tive120 or negativellg 121 roles in Belymphocyte activation and suggest that there are distinct nonoverlapping roles played by each of the Cbl family members C Protein Tyrosine Phosphatases The duration and strength of the signals generated upon BCR engagement depend on the balance between positive and negative factors Excellent reviews address the crucial role that the tyrosine phosphatases CD455quot123 and SHP71124 125 play in Belymphocyte activation Here we will provide a briefdiscussion ofthe functions ofthese molecules CD45 expression is required for normal Becell development particularly for the transition from the immature to the mature stage126 CD457 deficient mice are unresponsive to antiiBCR signals125 128 Data reveal that CD45 exerts its effects on BCR signaling by dephosphorylating the Ceterminal inhibitory tyrosine of Lyn eni suring its optimal activation123 Interestingly when CD45 mice are backecrossed to mice carrying the Tg transgene hen egg lyzozyme HEL negative selection of the HELebinding B cells is impaired and these cells are positively selected129 These data support a role for CD45 in setting the signaling threshold for the BCR and ultimately Becell tolerance The critical role that SHPl tyrosine phose phatase plays in lymphocyte regulation became evident from a study of the spontaneous mouse mutants point mutations resulting in anomalous splicing motheaten or viableemotheaten13 131 Lack ofSHpel or a catalytically inactive SHP71 leads to profound defects in Becell differentiae tion proliferation and survival reviewed in Refs 124 125 132 There is an overall decrease in the size of the Becell population and the cells are hypereresponsive to BCR stimulation displaying amplified Ca2 mobilization and increased MAPK Volume 23 Number 3 activity Mice also exhibit high autoantibody titers and immune complex deposition The overall exaggerated responses in the absence of a func tional SHP71 show that SHpelys role is to downregulate BCR signaling This occurs via the association of SHP71 with inhibitory receptors such as CD22 discussed below D Lipid Metabolizing Enzymes In addition to proteins BCR utilizes phosphorye lation and dephosphorylation of membrane lipe ids to transmit signals to the cytoplasm and nucleus PT3K and PLCW are two critical enzymes that utilize membrane lipids to generate second messenger molecules important for the activity of downstream signaling proteins The P13Kfamily consists ofthree classes and multiple isoforms133 We focus on class I PT3Ks which are the most important for Belymphocyte responses Class I PT3Ks consist ofap110 catalytic subunit p1100c p110B and p1105 isoforms and a p85 regulatory subunit five isoforms The regulatory subunit contains SH2 domains which enables recruitment ofPT3K to tyrosine phosphoe rylated proteins in the membrane133 PT3K is activated upon BCR engagement in a PTKe dependent manner49 It may also be recruited to the membrane via the cytoplasmic tail of CD19 see below Recently BCAP Becell adaptor for P13 K was shown to be phosphorylated by Syk and Btk upon BCR engagement and facilitates re cruitment of the p85 subunit of PT3K to the membrane134 However B cells from BCATH mice show no significant decrease in PT3K active ity although BCR signaling is impaired These data raise questions about the role of BCAP in PT3K regulation and suggest the involvement of other molecules PBK activation leads to generation of PT34P2 and PTP3 which serve as docking molecules in the plasma membrane for PHecontaining cytosolic proteins136 such as Btk137 PLC42138 Akt139 and Barn32140 By recruiting and bringing in close vicinity multiple signaling molecules PBK is able to directly and indirectly affect Ca2 mobilization Akt activation transcriptional regulation cell growth and survival 141 The critical role of Pl3K in Belymphocyte development and activation is evident in mice lacking the p850c regulatory subunit 142 or lacking or expressing an inactive form of the p1105 catalytic subunit 144 The development of B cells in such mice is impaired at the prof Becell stage B cells display defective responses to polyclonal Becell activators and mice are not able to mount a normal humoral response to Tl and TD antigens The p1105 mice also lack germinal centers in the spleen lymph node and Peyer s patches and develop a mild inflammae tory bowel disease143 Conn ol and attenuation of P13 Kemediated sig nals is dependent on SHZ domainecontaining inosie tol phosphatase SHIP which converts P1P3 to Pl34P2 and lns1345P4 to lns134P31 5 147 limiting the P1P3 available for recruitment of signale ing molecules Bolland et al demonstrated that Btk recruitment to the plasma membrane is dependent on the available PlP3 SHIP de ciency leads to increased Btk association with the membrane and consequently increased Ca2 response148 A similar mechanism is observed for SHlpemediated Akt inhibition1quot9 150 which utilizes its PH domain to be recruited to the plasma membrane SHIP s inhibie tory activities are dependent upon its recruitment to CD32 FclelBl51see discussion below Phospholipase Cy PLC y is another BCR stimulated enzyme that utilizes phosphatidyli inositols to generate two important second mesi sengers inositol 1457bisphosphate 1P3 and diacylglycerol DAG reviewed in Refs 152 153 Engagement of the BCR leads to PLC41 and PLCWZ activation but PLCWZ is more predomie nant in BCR signaling which requires tyrosine phosphorylation and relocalization from the cytoi sol to the plasma membrane15 156 PLC4 cone tains SHZ domains an SH3 domain and a PH domain which allow it to associate with a diverse range of molecules152 153 BCReactivated BLNK binds and recruits PLC42 to the membrane 7 making it available to Syk and Btk for phosphoe rylation and activation The products of PLC42 activation IF and DAG induce Ca2 mobilizae tion and PKC activation respectively141 PLC7 YZ C CiCnt mice are characterized by defects in the Belymphocyte population There is a decrease in mature B cells due to a block in proeBecell differentiation a disruption of the Ca2 response 156 and decreased proliferation in response to mitogee nic stimuli96 Overall the phenotypic abnormalie ties in these mice resemble those of Btk and BLNKrdC CiCHt mice889quotv102 which supports a role for the interactions among these molecules for proper Becell responses to antigen receptor engagement E SerineThreonine Kinases Activation of PLCry and Pl3K leads to the gene eration ofsecond messengers which are involved in the activation of the protein kinase C PKC family of serine threonine kinases The PKC family can be divided into three subfamilies depending on the second messengers required The convene tional PKCs PKCroc 3 31110 utilize both DAG and Ca2 for their activation relying primarily on the PLC4 pathway The activation of novel PKCs PKC75 8 T is DAGedependent and Caztindependent The atypical PKCs PKC7C N1 are not activated by either DAG or Ca and have been shown to be downstream of Pl3K158 More recently the PKD family has been described with PKCjJPKD as its main member 9 B lymphocytes express PKCroc 3 V 5 8 C T and p isoforms150 161 and BCR engagee ment has been shown to induce their activation as measured by translocation of PKC from the cytosol to the plasma membrane162 PKC activae tion has been shown to lead to activation of extracellulareregulated kinase ERK NFeKB cyclic AMP response element binding protein CREE and Elke1 reviewed in Ref 163 Generation of mice deficient for PKC7B demonstrate a critical role for PKC in Becell development and activation B cells lacking PKC7B display impaired BCRemediated prolife eration Examination of downstream signaling showed that PKC7B is required for the recruit ment ofthe IKE kinase lKK complex into rafts and consequently NFeKBemediated survival sige nals154 155 Recent studies have supported a crucial role for PKC75 in maintaining Becell tolerance and autoimmunity 167 Mice lacking PKC75 show an expansion in the Belymphocyte populae tion enlarged spleens and lymph nodes germinal center formation in the absence of stimulation increased H176 production and circulating aue Critim Reviewxw in ImmumUgy toantibodies These data show that PKC75 in contrast to PKC7B plays a negative role in BCR signaling Analysis of PKCC4 mice has also ref vealed an important role for this isoform in Belymphocyte activation albeit in different prof cesses158 169 Although the overall splenic structure of PKCC4 mice is preserved the marginal zone is anomalous manifested by smaller Becell fole licles Similar abnormalities are observed in perie pheral and mesenteric lymph nodes and Peyer s patches because ofimpaired segregation ofBe and Tecell populations B cells from these mice show impaired survival and proliferation in response to antieBCR stimulation impaired ERK and NFeKB activation and defects in the ability to mount a humoral response to Tl and TD antigens 169 Mitogeneactivated protein kinases MAPKs are a family of serineethreonine protein kinases that regulate various cellular activities including many in B lymphocytes BCR engagement leads to activation of the extracellular signaliregulated kie nases ERKs the celun Neterminal kinases GNKs stresseactivated protein kinases SAPK and p38 kinases153 170 members of the MAPK family Elegant studies using Becell lines deficient in specific protein tyrosine kinases have helped to delineate the pathways and molecules involved in activation of these kinases171 172 These studies show that Syk and Btk but not Lyn are required for ERK2 and INK activation Interestingly p38 activation is abrogated only in LynSyk doublee deficient cells171 Downstream of PTKs ERK activation is dependent on BCReinduced activae tion of the RasGTpeRafleMKKleErk signaling cascade163 BCR ligation results in the activation ofthe oncoprotein Ras by increasing the amount of Ras bound to GTPVHH The crucial role of Ras in Belymphocyte activation is evident in mice transgenic for a dominantenegative form of Ras which display a block in Becell development that is restored by expression of an active Raf 177 Interestingly expression of an activated Ras is sufficient to drive the r g i of 39 i activating gene RAGlfdeficient proeB cells in the absence of 1 chain expression underscoring the importance of Ras in differentiation and sur vival processes178 The activation ofRase RafeMKK culminates in ERK activation which links BCR ligation to various transcription factors including Etsel Ets72 Elkel Fos Egrel CREE and Volume 23 Number 3 NFAT163 Recent work has shown that ERK activation serves as a convergence point for Pl3K PLCry and Ras pathways 9 Interestingly upon BCR engagement ERK is primarily cytosolic where it can phosphorylate cytosolic kinases such as p90 5k whereas CD40 engagement leads to its nuclear localization180 The mechanisms involved in JNK and p38 activation upon BCR engagement are not well understood Similar to ERKJNKand p38 are part ofsignaling cascades characterized by consecutive phosphorylation of various kinases170 181 In B lymphocytes several molecules have been incor porated in MAPK SAPK and p38 activation including Syk171 Btk Rac1 PLCWZRSZ 183 Ba1n32184 SHP71ch185 GrbZ Ras172 BLNK102 PKCs186 MKK7187 and SEK1188 Activation of these MAPKs leads to their translocation to the nucleus where they can phosphorylate and activate their respective substrates including many tran scription factors which are important for gene expression75 163 The induction ofthe various trane scription factors requires temporal quantitative and qualitative regulation which is accomplished by the intricate integration of various signaling cascades depending on the differentiation stage and the signals B lymphocytes receive BCR CORECEPTORS A CD19 CD19 an 957kDa transmembrane member ofthe lg superfamily is expressed on B cells from early in development to the plasma cell stage of differene tiation CD19 was initially identi ed as a Becelli specific antigen189 and considered as a potential BCR coereceptor because it was found to coemodue late with the BCR19 The potential physiologic significance of CD19 became appreciated when it was discovered that its coiligation with the BCR 39 i quot lowers the threshold for BCRemedie ated Becell activation191 It was subsequently learned that CD19 functions as a signal receptor via a PTKe dependent pathway192 Since the late 1980s a number of laboratories have contributed consider able information on both the signaling mechani isms and biologic role of CD19 in the humoral response Here we review some of the highlights and most recent ndings a number of excellent recent reviews provide more detailed and compre hensive coverage of earlier studies193 195 CD 19 is normally associated at the cell meme brane in a complex with the complement recep tor CD21 and the tetraspanin CD81 it has been suggested that association with this complex via CD19 extracellular EC and transmembrane TM domains is important for CD19 signali ing1197 although the CY domain is directly responsible for signal transduction198 199 Mice deficient in CD81 show impaired CD19 surface expression200 but CD21 deficiency does not detectably reduce CD19 function201 suggesting that ligation of the complement receptor is not essential for CD19 signals This is consistent with the ability of agonistic CD19especific Abs to stimulate signaling events in 721270202 Howe ever a natural ligand for CD19 has never been convincingly identified so the relative roles of CD19 as an individual receptor versus in a come plex with CD21 and CD81 the natural in viva state remain unclear What are the important physiologic roles of CD19 in the humoral response The aforemene tioned early finding that CD197BCR coiligae tion lowers BCRemediated activation thresholds suggests that one role of CD19 is to enhance the effectiveness of a primary Becell response by inf creasing the magnitude of the signal delivered by antigen similar to the enhancement of Tecell receptoremediated activation by CD4CD8 Bee cause the affinity of the initial lgM produced upon first exposure to a particular antigen is lower coesignaling through CD19 may serve as a mechanism for increasing the probability that antigen binding will deliver a strong enough sig nal to initiate activation and clonal expansion However as CD19 functions can be complement receptoreindependent other roles and mechanisms of action are also likely Although expression ofCD19 does not appear to be important for development of convene tionalyy B2 B cells CD19edeficient mice show decreased numbers of 131203204 and marginal zone2 5905 B cells The role of CD19 in response to T1 antigens is inconsistent between studies and is thus currently unclear In different reports the response ofCD19 mice to T171 antigens is either inhibited203 or normal204 and to T172 antigens it 158 has been reported to show a decrease206 an inf crease207 or no change204 Developmental affects of CD19 in addition to inbred mouse strain back ground differences in response to distinct antigens may contribute to the difficulties in interpretation However responses of CD19edeficient mice to TD antigens are quite consistent in showing a marked decrease In all studies to date the lgG response to TD antigens is considerably compromised by the absence of CD19203204206207 In addition normal germinal center GC development in response to immunization with model antigens is comproe mised and although GC are formed in response to viral infection normal Becell memory does not develop208 It is thus clear that CD19 plays an important role in the development of a normal adaptive humoral response Much work has been done on the signaling mechanisms used by CD19 Tyrosineecontaining motifs in the relatively long CY domain of CD19 enable association with a variety of SH2 domaine containing signaling molecules One of the most prominent of these is Lyn the Src family kinase that has been reported to initiate CD19 signal ing209 However it has also been reported that CD19 signaling is independent of Lyn activae tion210 Additional PTKs with which CD19 assoi ciates include Fyn and ceAbl211 and these may serve redundant roles with Lyn in CD19 signal ing The CY tail ofCD19 also binds PL3K212213 ERICA2194 and adapter proteins such as Vav214215 CD19 can cooperate with the BCR and other receptors to activate MAPK ERK and SAPK pathways as well reviewed in Refs 193 194 This enhancement may be facilitated by the abile ity of CD19 like the BCR to localize to cholese terolienriched membrane rafts216 Because CD19 can associate with a wide vae riety of signaling proteins determining which signaling events are crucial to its biologic funce tion in Becell activation has been challenging Adding to the challenge is uncertainty about how closely ligation with anti7CD19 mAb the easiest way to initiate signaling in wing mimics initiation of CD19 signaling in viva The CY domain of CD19 contains 9 tyrosine residues which are evolutionarily conserved suggesting potentially important functions for each Different Y residues have been shown to regulate binding to distinct intracellular proteinsiY330 to Grb2217 Y391 to Critim Reviewxw in ImmmwUgy Vav217 Y421 to PLCWZ17 Y403Y443 to Lyn and Fyn and Y482Y513 to P13 K12 This sug gests that each of these associations plays distinct and important roles in CD19 signaling However recent studies in which CD19 transgenes contain ing various Y mutations were introduced into CD19 mice revealed an essential role only for Y482Y513 in restoring many CD19edependent functions These include development ofB1 and marginal zone B cells as well as lgG responses to TD antigens and normal GC development206 Interestingly however certain in vim BCRemee diated signals are not completely restored by Y482 Y513 More This could indicate that in vim ligation with antieBCR and anti7CD19 may not always reflect in viva biology but could also suggest a secondary more subtle role for addie tional P173 Keindependent signaling pathways in CD19 s various roles in the humoral response B CD21 CD21 is the complement receptor type 2 for iC3b C3dg and C3d CD21 is expressed onB lymphocytes and follicular dendritic cells FDC and together with CD35 is one of the alternatively spliced products produced by the C72 locus18 220 CD21 also binds EpsteineBarr virus EBV via its viral glycoprotein gp35022021 A 145kDa type I membrane glycoprotein CD21 consists of an ex tracellular domain of 15716 short consensus repeat domains a transmembrane region and a short cytoplasmic tail222 Early evidence of a role for CD21 in Belymphocyte activation showed that CD21 engagement synergizes with the BCR223 and that antibodies interfering with CR2 binding to its ligand abrogate the immune response to TD224 and T1225 antigens Later work showed that CD21 is part of a Becell surface signaling complex that also contains CD19 and CD8126 The role of CD21 in this complex is to increase the association of the complex with the BCR rather than transmit any signals which are provided by CD 19227 In this manner CD21 is able to link the complement system to the humoral immune response More recent work has suggested that the CD19CD21 complex is able to enhance the BCR response by enhancing and prolonging the association of BCR with lipid rafts28 Volume 23 Number 3 The phenotype of mice with a disrupted C72 locus underscores the importance of CD21CD35 in generation of a humoral response 231 CD21 CD35 deficient mice have reduced numbers ofB1 cells and GC and consequently an impaired hue moral response Fischer et al demonstrated a criti cal role ofCD21CD35 for survival ofB cells in GC independent of the af nity of the antigen recep tor232 Notably the levels of lgGZa lgGZb and lgG3 are signi cantly reduced 231 CD21CD354 show increased susceptibility to S pneummiae in fection supporting a role for CD21CD35 in linking innate and adaptive immunity to bacterial challenge31 Because CD21 is expressed onboth B cells and dendritic cells the contribution of each of the cell types was tested in reconstitution experie ments33 35 These studies showed that expression of CD21 by B cells is critical for the initial humoral response and lg classeswitching whereas expression on dendritic cells is important for the maintenance of antibody response affinity maturation and memory induction To address the role of CD21CD35 in the maintenance of selfetolerance Cr2 mice were bred with mice transgenic for soluble hen egg lysozyme sHEL and Becell negative selection was examined36 lnterestingly Cr2 HELibindi ing B lymphocytes fail to undergo negative selece tion and accumulate in the spleen and lymp node These data support an important role for CD21 in lowering the threshold for negative selection of autoreactive cells In addition ZNZ 7 mice deficient in CD21CD35 display exacere bated autoimmunity evident in splenomegaly glomerulonephritis and increased antinuclear antibody titers compared to ZNp7 mice These studies suggest a potential role for complement binding to CD21CD35 in the generation of autoimmunity lndeed Boackle et al were able to identify an altered C72 allele in the murine aue toimmune susceptibility locus in NZM2410 mice237 The C72 gene product in these mice is structurally different from the normal product and results in enhanced glycosylation of CD2 1CD35 The single nucleotide change observed in these mice introduces a new glycosylation site in the ligand binding domain which leads to decreased ligand binding diminished signaling in B cells as measured by the Ca2 response and impaired humoral response to TD antigens37 159 C CD22 CD22 is a sialoadhesin expressed exclusively on B cells and originally named Lyb8 lts expression structure function and signaling pathways have been the focus ofseveral comprehensive reviews in recent years193238239 Here we attempt to concisely summarize past ndings and discuss more recent data pertaining to CDZZ s role in the regulation of BCR signaling Mouse and human CD22 are 62 homologous in protein sequence Both cone sist ofan extracellular region ofseven lg domains a TM domain and a CY domain the latter has six tyrosine residues in both species reviewed in Ref 193 As a sialoadhesin CDZZ s initial pose tulated function was as an adhesion molecule particularly since its ligand is glycoconjugates cone taining OLZ 6linked sialic acid predominantly NeuAc0c26Gal3174GlcNac reviewed in Ref 23 8 It has been found that cell types ofhematopoietic origin especially T and B lymphocytes express greater amounts of CD22 ligands than do none hematopoietic cells193238 suggesting that one funce tion ofCDZZ is to target B cells to environments where they are likely to interact with T cells However it subsequentlybecame clear that CD22 also provides important regulatory signals for BCRe mediated Becell activation It was observed a decade ago that the CY tyrosines of CD22 become phosphorylated in B cells stimulated through the BCR240 As def scribed in an earlier section this process is depene dent upon the Src kinase Lyn and the phosphoe rylated tyrosines are within an lTlM motif Subsequent studies showed that CD22 physie cally associates with the BCR complex241 to which it can recruit the tyrosine phosphatase SHPel previously referred to as HCPPTpi 1C242 as well various kinases 244 PLCWZ l3 and the nucleotide exchange factor Vav245 Howe ever very recent work has shown that the rela tionship between BCR and CD22 described above does not exist if the BCR is lgG rather than lgM or lgD Ligation of surface lgG does not stimulate CD22 phosphorylation or SHPel ref cruitment246 A variety of complementary experie mental approaches including detailed cellular biochemistry as well as the analysis of CD227 deficient mice revealed that CD19 discussed above and CD22 provide counterbalancing regue 160 latory signals to the BCR and CD22 signaling has an overall negative role reviewed in Refs 193 238 239 247 Thus CD22 mice show features ofhypereresponsiveness to BCR signals2quot8v249 and a lack ofCDZZ phosphorylation contributes to the phenotypic features of the Lyn mouse 0 Ree cruitment ofSHPel to the BCR complex permits this phosphatase to suppress activation of the MAP kinases ERKZ p38 and INK counteracte ing their potential activation by CD19 reviewed in Ref 193 It has also been consistently observed that CD22 signals decrease Ca ux stimulated by the BCR251 252 possibly through inhibition of the phosphorylation of PLC7V This inhibition does not occur if an lgG BCR is providing the signal246 which may allow isotypeeswitched B cells to escape this method of negative regulation ofBecell activation Interestingly it has also been reported that in vim signaling to B cells viaMHC class II molecules can be reciprocally regulated by CD19 and CD22 signals 3 although the role of this regulation in viva is not yet clear Although the preponderance of evidence points to anegative regulatory role for CD22 signals more remains to be learned about this interesting signaling recep tor and it is possible that it also delivers important positive signals to the B cells Because CD22 does not have a single welle defined or easily isolated ligand in witm studies of CD22 as a signaling receptor have relied almost exclusively upon the use of agonistic anti7CD22 mAbs as a stimulus Whereas it is clear that much has been learned using this approach it is desirable to verify important signaling events and learn more about the physiologic interactions of CD22 with its natural ligands Several recent studies have ad dressed the knowledge gap of the role of the EC domain of CD22 in receptor function The high degree of sequence conservation of this region suggests an important role but its nature has been unclear Jin and colleagues studied the signaling function of CD22 mutants with defects in the putative sialic acidibinding domains and learned that inability to bind sialic acid impairs CD227 mediated downregulation of BCRemediated Ca2 ux particularly the early rise in Ca from exe tracellular sources 4 Using the complementary approach ofhigh affinity sialic acid analogs that inhibit binding of sialic acid to CD22 Kelm et al found that CD22 binding to this ligand is Critim Reviewxw in ImmmwUgy required for the receptor to inhibit BCRemedie ated Ca increases These studies introduce promising new approaches to a more physiologic initiation of the CD22 signaling pathway and begin to explore the role and nature of CD22 ligand binding D CD32 CD32 FclelB is an inhibitory receptor ex pressed on various immune cells including B cells macrophages dendritic cells mast cells and neutrophils5557 FclelB is a singleechain glycoprotein that contains an lTlM sequence in its CY tail which endows it with inhibitory properties The 13 amino acid sequence AENTITYSLLKHP was shown to be necese sary and sufficient for inhibition of the BCRe induced Cazt response and cellular proliferation58 Similar lTlM motifs are found in various other inhibitory receptors and data show a crucial role for the regulation of immune responses by coune teracting positive signals generated by ITAM econtaining receptors59 The inhibitory effects ochlelB are three fold two of which are lTlMedependent60 Coengagement of BCR and FclelB leads to phosphorylation of the tyrosine in the lTlM motif by Lyn kinase and thereby generation of a binding site for SHIP 8 SHIP recruitment attenuates the Pl3K pathway by hydrolyzing PIP thereby interfering with the association of PHecontaining molecules like Btk and PLCry and consequently blocking the Ca2 response Additionally SHIP has been shown to recruit the RasGApebinding protein p62d0k which is critical for FclelB inhibition of cell proliferae tion261262 FclelB is not able to inhibit prolife eration in Dokedeficient B cells while Ca in ux inhibition is intact262 supporting the existence of two distinct lTlMedependent inf hibitory pathways In addition FclelB dise plays lTlMeindependent inhibitory activity which is evident upon homoaggregation of the receptor FclelB engagement has been shown to induce apoptosis263 and this effect requires an intact TM domain rather than the lTlM motif is dependent on Btk and is blocked by SHIP64 Volume 23 Number 3 Selection of memory cells in the GC is dependent on BCR recognition ofimmune come plexes presented on dendritic cells The balance of positive and negative signals generated by BCR and FCVRHB respectively could lead either to stimulation inhibition or apoptosis This tightly regulated balance ensures approe priate immune responses and elimination ofselfe reactive cells Any disruptionto this process could contribute to the development ofautoimmunity The current model suggests that upon the ene counter of B lymphocytes with immune come plexes FclelB is necessary to counteract signals emanating from the BCR Such negative regue lation is important for preventing the develope ment of autoimmunity57 This is evident in the study of mice deficient for FclelB The hue moral immune response to Tl and TD antigens is elevated in chRllB mice More imbor tantly mice with certain genetic backgrounds are are more susceptible to autoimmune disease which is evident by the presence of autoantibodies to nuclear antigens and autoimmune glomeruloe nephritis266 In addition an FclelB deficiency exacerbates other autoimmune diseases such as type ll collageneinduced arthritis257and Goodpasture s syndrome268 IV TDEPENDENT BCELL ACTIVATION Stimulation of the B cell via its BCR and coe receptors summarized in Figure 1 provides crue cial signals to the process ofantigenespecific Becell activation However the development of an eff fective humoral memory response requires the B cell to receive contactemediated signals from the activated T lymphocyte This requirement exerts important regulatory control over Becell activation in a number of ways In normal indie viduals polyclonal activation ofB cells by contact with T cells is very limited although the two cell types are capable of stimulating one another through a variety of nonpolymorphic receptor ligand pairs see below This suggests that coge nate interactions between antigenepresenting B cells and activated T cells increases the efficiency of delivery of nonecognate signals between the two cells an hypothesis supportedby several stude ies18 269270 A number of mechanisms could prof vide this increased efficiency BCR signals ene hance Becell responsiveness to Tedependent activation signals and induce increased expression of surface molecules contributing to antigen pref sentation Direct interaction via MHCiTecell receptor binding can also increase BecelliTecell proximity amplifying delivery of both contacte mediated signals as well as soluble molecules Signals delivered to the B cell through ligation of MHC class H molecules have also been shown to enhance both antigen presentation and Becell activation and to cooperate with both BCR and T CCll dCl iVCd signals discussed below Regulation of contactemediated Becell activae tion may be important not just to promote desirable activation events but also to prevent autoimmunity It has been demonstrated that deletion of selfereactive Tecell clones appears more rigorous than that of autoreactive Becell clones especially if the amount of autoantigen is limiting CORRECT 1271 If a cognate autoantigene specific Tecell clone does not exist an autoreactive Becell clone has few opportunities to become activated and produce higheaffinity pathogenic autoantibodies The importance of contact mediated signals in the development of autoime munity has been highlighted in several published studies272273 Thus contactemediated signals in antigenespecific Becell activation both increase the effectiveness of adaptive humoral responses and decrease the potential for activation of self reactive B cells Below we discuss the current state ofknowledge about key signals delivered to B cells through contact with activated T cells A MHC Class II An earlier paradigm held that Tecell lymphokine production alone or in combination with BCR signals is sufficient to account for the contribue tion of T cells to TD Becell activation274 275 However when more stringently separated reste ing B cells were studied it was revealed that although soluble factors play key roles in Becell 162 activation contactemediated signals from the T cell are also critical reviewed in Ref 276 The first of these signals to be identified was MHC class H Ligation of Becell class H molecules induces early biochemical signaling events as well as subsequent effector functions including prolif eration differentiation reviewed in Ref 277 and enhanced antigen presentation278 281 Both CY and TM domains of the molecule have been demonstrated to contribute to signaling events282 283 Although TD Becell activation can occur in the absence of class H expression284 class H signaling enhances both BCR and CD40 sig nals269 and may contribute to the activation of CD407def1cient B cells Additionally it has been shown that class H signals can inhibit CD957 mediated Becell apoptosis286 an interaction that may promote the survival ofB cells in the germie nal center Thus by enhancing the effectiveness ofother Becell activation signals class H signaling may serve a regulatory role by preferentially prof moting the TD activation of cognate antigene presenting B cells rather than bystander B cells Consistent with this role is a report that class II signaling may in part be regulated by two BCR coreceptors CD19 and CD22 3 and may even utilize components of the BCR signaling come plex lgeoc and lge in its signaling pathway287 Additionally it has been shown that following its engagement class H localizes to cholesterol and glycosphingolipideenriched membrane microe domains or rafts 288 potential sites ofassembly of membrane signaling complexes CD40 also locale izes to membrane rafts following its ligation in B cells289 and physical association between CD40 and MHC class H subsequent to their engagee ment on B cells has been demonstrated290 Undere standing how physical interactions between class H and other transmembrane receptors affect the ultimate nature and strength of regulatory signals delivered to the B cell is important for understand ing the physiologic role ofclass H signaling in TD Becell activation B Adhesion Molecules The expression ofa number ofadhesion molecules is increased on B cells as a result of initial activate ing signals and enhanced expression of these Critim Reviewxw in ImmmwUgy molecules amplifies BiT interactions and Becell activation Both B and T cells express lCAM71 CD54 and LFA71 CD1 1aCD18 which bind each other and can thus mediate both homotypic and heterotypic adhesion Enhanced B celliTecell contact can optimize activation signals delivered during TD Becell activation and adhesion mole cules can also retain B cells in specialized environe ments in which they receive important regulatory signals91 Potential roles played by direct signal ing to the B cell via adhesion molecules is less clear Earlier studies suggested that both CD11a CD18 and CD54 can directly provide Becell actie vation signals 293 and it has been shown that such signals could contribute to enhanced Becell antigen presentation9 Signals via adhesion recep tors can also interact with other Becell signal receptors It was shown that such signals cooperate with CD407mediated activation294 and it was recently reported that CD54 signals can synergize with BCR signals to upregulate the costimulatory molecule CD80 Additionally CD5 4mediated upregulation of Becell class H expression was shown to correlate with activation of the Src family kinase Lyn and MAPKs96 A clearer understand ing of how and in what physiological circume stances adhesion molecules can signal to B lymphocytes and how these signals coordinate with other TD signals will help to fill in the entire picture of how T713 interactions can regui late Becell activation C CD72 Earlier studies reported that antibodyemediated engagement of the CD72 molecule on B cells induces upregulation of MHC class H expression proliferation and prolonged Becell survival and it has been shown that these positive signals utilize the MAPK pathway97 However for quite a few years the natural ligand for CD72 proved elusive More recent studies identified this ligand as CD100 a member of the semaphorin family expressed on both B cells and activated T cells and known to participate in neuronal regulation98 Engagement of CD72 by CD100 enhances Becell activation mediated by CD40 and blocking this interaction inhibits Tedependent lgG production although lgM production is unaffected98 Complementary Volume 23 Number 3 studies in CD 100deficient mice show that CD 100 expression is required for the normal development ofB1 B cells as well as for development of high affinity lgG responses to TD but not Tl antie gens299 Results also implicate CD1007mediated CD72 signals as important to antigen presenta tion and potentially responsible for inducing the dissociation of the phosphatase SHP71 from CD7298 299 Recent studies suggest that CD72 expression when CD100 is not present inhibits BCRemediated lgeoclge activation via its assoe ciation with SHELL300 Thus the emerging pic ture of CD72 suggests a molecule whose expres sion itself provides negative regulation of BCR signaling but when engaged by its ligand effects BCR signals positively D Members of the TNFR Superfamily The tumor necrosis factor receptor TNFeR fame ily of molecules is a large diverse group of mole ecules that participates in the regulation of cellular activation development and programmed cell death301 B lymphocytes express a number of members of this family which have been shown to participate in and regulate Becell activation in a variety of ways The receptors and their known functions in Becell regulation are discussed in the following section 1 CD40 CD40 was initially characterized as a potential tumor antigen on a bladder carcinoma302 Ale most a decade later the physiological roles played by CD40 in Belymphocyte activation became clear when it was discovered that defects in the CD40 ligand CD154 cause the rare Xelinked human immunodeficiency disease HyperelgM Syndrome HIGM3 3 305 byblocking delivery of CD40 signals HlGM patients suffer profound defects in humoral immunity despite the pres ence of normal numbers of peripheral B cells The term HIGM refers to the normal or abnorr mally high serum lgM levels seen in such pa tients Although antibody responses to Tl anti gens are intact responses to immunization with TD antigens and the production of switched isotypes oflg are greatly decreased306 During the same time period CD154 was found to be the factor in activated Tecell membrane preparations responsible for inducing a variety of Becell actie vation events307 310 Subsequently CD40 and CD154idC CiCHt mice were produced using gene targeting tech nology The phenotypes of both strains of mice are quite similar to each other and to HlGM patients indicating a nonredundant receptor7 ligand pair311 313 Human HlGM is a rare disore der so the availability of such patients for def tailed study is quite limited The manifestation of the disease early in childhood additionally limits the amount of biological material available for study as do ethical considerations Thus the mouse model systems have proven quite valuable in allowing more rapid accumulation of informae tion on the physiologic roles of CD407CD154 interactions Studies in mice as well as work performed ex W720 with freshly isolated B cells and Becell lines demonstrated that CD40 sig nals induce enhanced expression of surface mole cules involved in T713 collaboration costimulatory molecules adhesion molecules and others Dee fective CD40 signals thus result in defects in antigen presentation by B cells macrophages and dendritic cells contributing to deficiencies in celle mediated as wel as humoral immunity 14419 Studies with CD40 and CD154id CiCHt mice revealed the importance of CD40 signals in TD Becell activation However CD40 is also ex pressed on macrophages and dendritic cells for which its signals that enhance antigen presentation are critic data interpretation in the knockout mice can be complex In this regard more simplified in vim model systems have been helpful in determining the specific direct effects of CD40 signals on B7 cell activation Although Tl antigen stimulation can induce normal Becell expansion in CD407 deficient mice in vim studies demonstrated that the CD40 signal can directly induce Becell prolife eration and can synergize with signals through the BCR andor the H174 receptor259 324 325 Al though Tl antigens can induce lgM production in mice or humans lacking CD40 signals CD40 signaling can strongly promote Becell lgM prof duction259 324 325 Recently it has been shown that various soluble factors induced by CD40 signals 3173143153173207323 so 164 including H176 and TNFioc contribute to this lgM production325 329 In addition to the aforementioned lymphoi kines CD40 ligation on B cells can induce their production of lymphotoxinealpha330 332 H1710333 IL7 12334 and chemokines335 These factors can regulate Becell isotype switching discussed below migration and antigen presentation capacity What are the molecular mechanisms by which CD40 signals to B lymphocytes Because CD40 has to date been much more extensively studied than additional members of the TNFeR family that contribute to Becell ac tivation discussed below we will discuss the CD40 signaling pathway in detail the events discussed in the text are summarized in Figure 2 However many ofthese events are being revealed to have parallels in Becell signaling via other TNFeR family receptors Members ofthe TNFeR superfamily as well as certain other receptors utilize distinct but overlapping sets of cytoplasmic adapter proteins calledTRAFs TNF R SSOCiEICd factors to def liver signals to cells The first TRAP found to associate directly with CD40 was TRAF3 inie tially referred to as CD40 binding proteinyy Sube sequently CD40 was also found to directly bind TRAFs 2 and 6 and to associate with TRAFl principally via heterodimerization with TRAFZ for a recent review see Ref 336 It has also been reported that CD40 binds TRAF5337 but a par allel report reached an opposite conclusion338 TRAF54 mice show modest alterations in CD40 signaling339 but since CD40 binding to TRAFS has not yet been demonstrated in B cells it is unclear if this phenotype is a direct or indirect result ofthe lack ofTRAFS in all cells and tissues of this mouse With the exception ofTRAFl all TRAF molecules contain a Zincebinding RING finger domain at the Neterminus and removal of this domain renders the TRAP unable to promote signaling and able to inhibit normal TRAF funce tion as a dominant negativeyy DN340 Many studies have sought to understand the physiologic roles ofTRAFs in CD40 functions in B cells by asking which TRAFs contribute to these functions A number of early studies approached this question by transiently overexpressing both CD40 and specific TRAFs Wt or DN together with various reporter gene constructs in the easily Critim Reviewxw in ImmumUgy CD40 NFKB NFAT NFlL6 BSAP E2F others AP1 others FIGURE 2 CD40mediated signaling pathways It has been clearly demonstrated that NFKB and stressactivated protein kinases eigi p38 and JNK are activated by CD40 but how interaction with TRAF molecules leads to these events is still uncleari Potential intermediary steps are outlined Multiple transcription factors are activated by CD40 but in most cases the events leading to their activation have not been determined transfectable epithelial cell line 293 However some major caveats apply to the interpretation of data obtained by this approach CD40 binds at least 4 distinct TRAFs and 3 ofthese TRAFs 1 2 and 3 have overlapping binding sites336 Thus overexpression significantly alters receptor inter action with all of the TRAFs binding near this location Additionally it has been recently shown that CD407TRAF binding defined in such sys tems does not necessarily re ect binding require ments seen at normal protein levels in B cells341 Finally physiologically important functions of CD40 specific to B cells cannot be assessed in other cell types For these reasons we will restrict our discussion in this review to information gained about CD407TRAF function in studies that actur ally examined B lymphocytes Studies of B cells expressing structural mur tants of CD40 revealed that CD40 effector func tions are regulated by several different structural motifs in the CD40 CY domain342 345 Several of these motifs were ultimately found to correspond Volume 23 Number 3 to TRAF binding sites indicating that TRAFs 2 and 6 play important positive roles in CD407 mediated Brcell activation3 35O Interestingly binding of the known TRAFs cannot account for all the CD40 signaling motifs found suggesting that additional CD40 binding proteins remain to be discovered To attempt to directly investigate the causal role of different TRAFs in CD40 signals mice genetically deficient in individual Fs were created However TRAFs interact with many members of the TNFrR superfamily playing a variety of roles in normal physiology and development340 It is perhaps thus not surprising that mice made deficient in TRAFs 2 3 and 6 die in man or shortly after birth and have severe abnormalities in multiple organs and tissues351 353 This largely precludes their use in obtaining clearly interpretable information on TRAF roles in CD40 signaling to mature B cells To attempt to circumr vent this limitation alternate approaches have been used As mentioned above CD40 molecules with targeted mutations in TRAF binding sites have been studied to assess TRAF dependence of 165 particular CD40 signals in B cells this approach has been widely used and provided considerable information342 343 345 346 354 The approach has also been adapted to in viva models by inserting mutant CD40 transgenes into CD40 mice355 357 Howe ever although this approach allows potential study ofthe roles ofindividual TRAFs in in viva Becell responses discordant conclusions about such roles in distinct studies 355357 illustrate that this model also has technical caveats A number of factors may have contributed to complications in data interpretation and different conclusions in the studies cited above These include using transgenic receptors with the external domain of human CD40 which has lower binding affinity for mouse CD154 than does mouse CD40 significant varia tion in levels ofCD40 expression between various Wt and mutant molecules overexpression of par tiallyedefective CD40 molecules could obscure defects in signaling and differences in the spe cific antigens studied in immunization experie ments CD40 contributions may not be the same for responses to all TD antigens Additionally assumptions made about the TRAP binding char acteristics of each mutant transgene need to be verified in the transgenic B cells themselves For example a particular point mutant in which the T residue of the PXQCT motif in the CD40 CY tail has been changed to an alanine has been widely believed to lack the ability to bind either TRAFZ or TRAF3 on the basis ofdata obtained with in vim binding methods and overexpression studies in epithelial cells However when we examined this mutant CD40 molecule expressed in B cells we were surprised to discover that its binding to TRAFZ is impaired but not elimie nated and its binding ofTRAF3 is not detectably different from that oth CD40341 Thus it is not valid to use this mutant to draw conclusions about the TRAF3 independence of particular CD40 functions and its ability to deliver a particular signal also does not indicate complete indepene dence from TRAFZ Finally even in the beste designed CD40 structureifunction studies data interpretation cannot completely eliminate the possibility that in perturbing binding ofa known TRAF or TRAFs there is also altered binding of additional unknown proteins or inadvertently permitted binding ofa factor that does not assoe ciate with Wt CD40 Structurtrfunction approaches 167 using CD40 mutants have thus provided many valuable clues to TRAF function but they cannot by themselves provide definitive information To produce alterations in TRAFs directly while circumventing the low viability of TRAFH mice investigators have exogenously expressed N TRAF molecules in Becell lines3quot7350358359 or mice360 These studies have also provided useful clues about TRAP function However as noted above overexpressing a Wt or DN TRAF mole ecule does not just inhibit the binding of its corresponding endogenous TRAP it also alters the entire stoichiometry of the CD40 signaling complex and thus this approach also yields come plications in data interpretation Recently we have used a method of homologous recombinae tionebased gene targeting in somatic cells to prof duce TRAFH Becell lines Initial studies of these B cells has revealed that TRAFs 2 and 6 serve both redundant and unique roles in CD40 signals to B cells This approach allows transfection ofthe cells with both mutant CD40 molecules as well as Wt and mutant TRAFs and thus has the potential to provide valuable additional information about the roles of TRAFs in CD40 signaling to B cells361 The picture emerging from all these varie ous complementary approaches is that TRAFs 2 and 6 provide important and partially redundant roles in CD40 functions in B cells The roles of TRAF3 may be both positive and negative and the roles ofTRAFl are not at all well understood further investigation is needed to determine these roles more precisely How does CD40 regulate TRAP function in B lymphocytes Following CD40 ligation TRAFs 2 and 3 are rapidly recruited to the cell membrane362 which allows localization of TRAFs to cholesterole rich membrane microdomains or lipid rafts289 Definitive determination of the absolute require ment of raft localization for TRAP function has been difficult because commonly used cholesteroli depleting reagents were found to compromise membrane integrity and activate stresseactivated protein kinases SAPKs289 one of the first steps of CD40 s signaling pathway in B cells reviewed in Ref 363 Following raft localization associae tion with CD40 in B cells induces degradation of both TRAFs 2 and 3 but not TRAFs 1 or 6289364 The degradation ofboth TRAFZ and TRAF3 is largely dependent upon TRAFZ binding to Critim Reviewxw in ImmumUgy CD40364 requires the TRAFZ RING domain and is dependent upon ubiquitination355 The ampli ed and sustained Becell signaling induced by CD40 s virally encoded oncogenic mimic lae tent membrane protein 1 LMPI correlates with a defect in LMPl s ability to induce TRAF dege radation364 whereas blocking CD407mediated TRAFZ degradation leads to LMPlelike changes in the magnitude and duration ofCD40 signals to B cells355 Taken together these observations sug gest that TRAF degradation is an important means by which CD40 regulates TRAP function and signaling Understanding how the degradation of TRAFs 2 and 3 is initiated and how CD40 regue lates TRAFs 1 and 6 are areas of interest for further investigation TRAFs themselves have no known enzyme activity they serve as adapter proteins in signale ing TRAP aggregation initiated by trimerization of CD40 that occurs upon engagement by CD154 leads to interaction of TRAFs with downstream signaling molecules At least several distinct CD40 signaling pathways appear to be initiated by TRAFs Two lead to the activation of SAPKs JNK and p3 8 and a third leads to NFeKB activation Other kinases may be involved in these pathways and or additional pathways Germinal center kinase GCK 3 and related enzymes367 can interact with the TRAP domain ofTRAFZ in B cells and may contribute to CD407inducedJNK activation The mitogeneactivated protein kinase family may also contribute to CD40 signaling pathways GCK can bind MEKKI an MAPK upstream of INK358 370 and TRAFZ may also interact with the MAPK ASKel which could induce activation of JNK and p38371 However these latter interactions have yet to be confirmed in B cells Additional kinases may contribute to CD40 signal transduction CD40 signals to B cells can activate the Src family kinase Lyn and induce the phosphorylation of both phosphatidylinositole3e kinase and phospholipase CYZ in human B cells372 Recently CD40 signals were also shown to actie vate the serineethreonine kinase Pimel in mouse B cells373 Which kinase or kinases initiates the NFeKB pathway in CD40 signaling The activation of NFeKB by TRAFZ and TRAF6 was initially crede ited to NlK374375 an MAPK family member Volume 23 Number 3 NlK can phosphorylate and activate the IKE kie nase lKK complex which phosphorylates inf hibitors of NFeKB IKE proteins thus leading to their ubiquitination and ultimate degradation 376 Although overexpressed NlK enhances NFeKB activation in 293 epithelial cells there is no direct evidence that it specifically mediates CD407mediated NFeKB activation in B lymphoe cytes Alymphoplasia aZy mice expressing a mutant form of NlK377 show certain defects in Becell activation However these defects are not specific to CD40 responses B cells from 3aZy mice also fail to respond normally to LPS and BCR signals378 Additionally mice completely deficient in NlK show defects in response to the TNF family member lymphotoxin 3 but do respond to CD40 signals379 Thus the role played by NlK in CD40 responses may be indirect Interestingly MEKKI has also been shown able to phosphorye late and activate the lKK complex380 It is also important to note that the interactions of TRAFs with MEKKI NlK and other kinases have ale most exclusively been demonstrated under nonphysiological conditions in which both TRAFs and candidate kinases are transiently overexpressed in epithelial cell lines It thus remains to be determined which ifany of the potential TRAFi interacting kinases when present at physiological levels are important players in CD40 signals to B cells Several other kinases have also been posited to contribute to CD40 signal transduction CD40 engagement has been shown to activate the Src family kinase Lyn and to induce the phosphoryi lation of both phosphatidylinositole3ekinase and phospholipase CYZ in human B cells372 Recently CD40 signals to B cells were also shown to activate the serineethreonine kinase Pimel373 However it is unclear how these enzymes fit into the overall mechanism ofCD40 signal transduction a quese tion of great interest CD40 signaling to B cells induces production of many types of proteins that play roles in the immune response These include lymphokines and chemokines immunoglobulins and cell meme brane receptorsligands and other Becell activae tion molecules such as MHC class H and CD70 see below To date these increases have all been shown to correlate with enhanced mRNA exprese sion Most ofthe earlier studies on CD407induced 168 transcriptional regulation in B cells have focused on activation ofmembers ofthe RelNFeKB fame ily oftranscription factors The absence in mice of the NFeKB subunit RelA causes embryonic lethale ity381 whereas mice de cient in RelB have severe abnormalities in hematopoietic development and widespread in ammation of multiple organs382 p52 mice have defects in the organization of their lymphoid tissues383 It is therefore dif cult to use any of these mice to clearly de ne the roles of NFeKB in CD40 signaling to normal B cells Mice de cient in p50 or ceRel subunits survive to adulte hood and have relatively normal numbers of he matopoietic cells However both strains have defects in antibody production7384 385 and p507 de cient mice have defective CD407mediated NFeKB activation386 However B cells from these mice have developed in an abnormal environe ment because NFeKBimediated transcriptional regulation participates in so many cellular func tions A complementary approach that avoids this problem is to inducibly inhibit NFeKB activation in B cells using inducible expression ofa form of IKBoc that cannot be phosphorylated and def graded When CD407mediated NFeKB activation was blocked in several mouse Becell lines using this technique it was found that NFeKB activae tion is critical for some but not all CD40 effector functions387 Enhanced production ofCD80B7e 1 is highly dependent upon NFeKB activation upregulation ofCD23 CD95 and CD54 is par tially NFeKB lependent and upregulation of CD11a does not require NFeKB CD407mediated lg production is present but markedly diminished when NFeKB translocation is inhibited387 The activation ofJNK by CD40 is independent ofthe activation of NFeKB387 but CD407mediated Pime 1 kinase induction appears to require NFeKB ac tivation373 Whereas CD407mediated H176 prof duction requires TRAF association it is independent of CD407mediated increases in nuclear NFeKBRm388 although basal levels of NFeKB are required389 CD407mediated transcrip tional regulation thus involves transcription face tors in addition to andor working cooperatively with NFrKB The factors BSAP and Stat6 can also be actie vated in B cells by CD40 ligation 391 and may promote transcription of the germline 8 gene that precedes class switch recombination to lgEm393 169 Stat6 and NFeKB may also interact potentially contributing to the synergy between CD40 and H174 signals in the induction of germline 8 tran scription394 CD40 signaling to B cells can stimue late activation of AP71 NFeATf and E2F3 However the functional roles of these factors in CD407mediated Becell functions have not yet been explored Because CD407mediated induction of H176 gene expression and production in B cells does not require increased NFeKB activation388 this promoter provides an attractive model for exploring the involvement of additional transcription factors in CD40 function We have recently found that the transcription factors AP71 and NFelLe both ap pear to play important roles in CD407mediated activation of the H176 gene as well as subsequent lgM production in B cells389 It has also been suggested that both the germline 8 and CD23 promoters contain yet unidenti ed regulatory elee ments speci c to CD407mediated gene expresi sion397 398 Additional transcriptional regulation of target genes by CD40 remains to be characterized 2 CD120b TNFRZ The cytokine TNF has been shown to promote antibody production by B cells399 402 although earlier studies did not determine whether CD120a TNFR1 or CD120b TNFRZ or both were responsible for delivering Becell activation signals More recent ndings show that B cells express little or no CD120a so CD120b is primarily responsible for delivering TNF signals329 of par ticular interest CD40 signals induce both human and mouse B cells to produce TNRW 331 and this TNF makes a signi cant contribution to CD407 induced lgM production329 This TNFemediated signal was shown to require the binding ofTRAFZ to CD120b329 Further studies are needed to more completely elucidate the roles played by CD120b in Becell activation and the molecular mechae nisms used by this receptor 3 CD137L 41BBL CD 137L 471131311 expressed on B cells interacts with CD137 4711313 expressed on activated T cells CD137 signalng has been shown to provide ime Critim Reviewxw in ImmumUgy portant costimulatory signals to the T cell ref viewed in 403 but whether CD137L has an in viva role in Becell signaling is still unclear Earlier in vim studies showed that ligation of CD137L enhances the Becell proliferative response to antie 1 antibody404 but the primary and secondary antibody responses to a TD viral antigen are intact in CD137LidC CiCHt mice4 5 However a more recent study ofCD137L mice showed a reduce tion in lgG2a and lgG3 produced in response to the model antigen KLH406 Thus while it cur rently appears that the primary function of CD 137L is to stimulate CD137 signaling in T cells this receptor may also regulate TD Becell activation in particular situations 4 CD134L 0X40L In recent years considerable interest has been shown in the role ofthe TNFeR family molecule CD134 0X40 in Tecell costimulation Howe ever earlier studies showed that the ligand for CD134 which is expressed on activated B cells can itself send signals to B cells that promote proliferation and differentiation 07408 Studies of CD134LidC CiCHt mice reveal that TD lgM prof duction is normal but there is reduced production of switched lg isotypes409 However in contrast to CD40 mice which lack GC GC formation can proceed in the absence ofCD134L signals408 This suggests that these signals play their major role in production of an effective secondary antibody ref sponse rather than in development of memory B cells An additional role for CD134L was suggested by the finding that CD134 stimulation of B cells enhances the rate of lgG production stimulated via CD40 1L4 and 1L71041 5 CD27 and CD70 CD27 expressed by a subpopulation of peripheral human B lymphocytes and germinal center B cells has used in recent years as a marker of memory B cells reviewed in Refs411 412 The ligand for CD27 CD70 is expressed byT lymphocytes relae tively late in their activation413 and has also been found on activated B cells CD40 signals can participate in its upregulation415 CD27 signals Volume 23 Number 3 appear to be particularly important in the terminal differentiation of B cells into antibodyesecreting plasma cellsm 418 and are thought to be important for lgG but not lgM productionquot1quotv419 lntereste ingly CD27 is also expressed by many T lymphoe cytes where one of its roles may be to modulate the effects of CD70 on B cells by acting as a decoy receptor419 Like other TNFeR family members signaling by CD27 is mediated at least in part by TRAP molecules TRAFs 2 3 and 5420 Al though CD27 delivers some signals in common with CD40 such as activation of NFeKB and INKWO 421 additional unidenti ed signals and the timing of CD27 expression presumably contribute to its unique activities in Becell differentiation 6 CD30CD153 The contribution of CD30 and its ligand CD153 to Tecell lependent Becell activation is not well understood CD30 appears to be expressed at low levels on resting B andT lymphocytes and can be upregulated by immunological stimuli422 CD30 can be cleaved from the cell surface and elevated levels of the soluble form have been detected in sera from patients with autoimmune diseases viral infections and various types of cancer422 Unlike other soluble monomers of the TNFeR family soluble CD30 retains a reasonable af nity for its ligand suggesting that it may have some type of activity in ongoing immune responses423 CD40 signals upregulate CD30 expression on B lymphoe cytes but the expression can be downregulated by signaling through the Becell antigen receptors H176 or Hr12424 One important role of CD30 signals in B cells may be in suppressing CD407 stimulated lg isotype switching when a specific antigenic stimulus is absent hence the negative regulation of CD30 expression by BCR424 The CY domain of CD30 potentially interacts with TRAFl TRAFZ TRAF3 and TRAF5425 and in at least some cell types is able to stimulate the activation of NFeKB JNK and p38quot25 428 Like CD40 CD30 signaling may result in the degrae dation of TRAF molecules potentially altering signaling by other members of the TNFR family such as CD40 or the TNF receptors429 Although CD30 appears to play negative regulae tory roles in B cells signaling through CD30 in 170 CD4 T cells has been shown to be a costimulus for cell proliferation430 431 including the production of ILel Interestingly CD153 signaling in B cells also appears to inhibit isotype switching432 Although the proximal signaling events initiated by CD153 remain uncharacterized signals from this receptor appear to inhibit CD40 signaling and transcription of mRNA encoding Blimpel a n anscription factor involved in the development of plasma cells and enhance the binding of the B cellespeci c activator protein a repressor of Ig transcription to the immunoglobin 3x enhancer432 and cytokine production 3428 7 BAFF and APRIL Recently two novel TNF family members were identified and have been shown to contribute to the establishment of humoral immune responses One of these proteins termed BAFF alternatively Blys THANK ZTNF4 or TALLel is the sube ject of an extensive recent review433 Expressed by macrophages and dendritic cells the primary func tion of BAFF appears to be in preserving the viability of immature B cells in the spleen during their maturation from the transitional type 1 stage to type 2 BAFF also contributes to the maintee nance of the mature Becell population BAFF transgenic overexpressing mice exhibit Becelli mediated autoimmune diseases perhaps because of the rescue of autoreactive clones that would other wise die during development BAFF may also help to prevent apoptosis of B cells involved in an ongoing immune response434 Potential receptors for BAFF include BCMA TACI and the more recently identified BAFFeR The function of BCMA is not yet understood but BAFF activity is not impaired in BCMAedeficient mice TACIe deficient mice display defects in humoral responses to TI72 antigens but this effect is likely related to disruption of signaling initiated by APRIL see below Like BAFFedeficient mice BAFFR mice have virtually no mature B cells illuse trating the important roles for both BAFF and BAFFR in Becell development This also illustrates that even though BAFF can potentially bind BCMA and TACI these receptors are uni able to substitute for the function of BAFFeR Although BAFF is able to bind TACI and BCMA at least one other ligand APRIL exists for these two receptors APRIL appears not to bind BAFFeR but may have yet another uncharacterized receptor l35 436 Together APRIL transgenic mice435 and TACIedeficient mice m 438 indicate that one biological role of this ligande receptor pair is in the promotion of humoral responses to TI72 polysaccharide antigens TACI also appears to contribute to the regulation ofBi cell homeostasis since TACIedeficient mice dise play expanded Becell compartments One might expect therefore that APRIL would reduce Becell numbers when injected or expressed from a transgene However this is not the cased 439 suggesting that APRIL may not contribute to TACIemediated Becell homeostasis 8 CD95 Fas CD95Fasemediated regulation of the immune response has been discussed in general by several recent reviews 0 441 Here we focus on the spee cific effects of CD95 on the activation of B lymphocytes One ofthe ways in which Becell responses are normally limited involves CD957 mediated apoptosis During the latter stages of CD407mediated Becell activation CD40 signals induce CD95 upregulation on the responding B lymphocytes which then become increasingly susceptible to apoptosis induction by CD95L expressed by activated T lymphocytes442 445 Defects in CD95 signaling or expression of CD95L result in dramatic dysregulation ofantie body responses in viva resulting in hypere gammaglobulinemia splenomegaly lymphade enopathy and autoimmunity lquot5 448 However effective Becell activation requires that cells be resistant to CD95emediated apoptosis until an effective antibody response Ig isotype switching and somatic hypermutation have taken place Additional signals provided to B cells during their interaction with antigen and T lymphoe cytes appear pivotal in this ability to avoid apoptosis during the active phases ofan antibody res onse285quotlquot9 454 Signals provided by follicular dendritic cells also appear to play an important role in the regulation of apoptosis of B cells455 457 How can such signals prevent or rescue B cells Critim Reviewxw in ImmumUgy from CD95einduced apoptosis One site ofearly intervention may be during the assembly of the CD95 signaling complex at the cell membrane Assembly of the deatheinducing signaling come plex DISC can be disrupted or inhibited in several ways BCR and CD40 signals have been shown to increase expression ofceFLTP FLTCEe inhibitory protein a proteolytically inactive homoe logue of caspase78458quotl59 Caspase 8 is the first cysteine protease to be activated in B cells by CD95 ligation In the presence of elevated levels of ceFLTP CD95 ligation results in normal Fase associated death domain protein FADD recruite ment but the subsequent recruitment ofcaspasee 8 is substantially decreased and apoptosis is inhibited or delayed Relevant to this mechanism it has been demonstrated that BCR signaling is able to block recruitment of FADD to CD95460 This inhibition is observed even if BCR and CD95 signals are delivered simultaneously is indepene dent of de 7mm protein synthesis and may contribe ute to the inhibition of apoptosis in B cells ref sponding to specific antigen until the antigen is cleared This couldbe important in the generation of longelived memory B cells in the germinal center The activation of PT3K and Ak PKB can also inhibit CD95emediated Becell apoptosis in some situations461 although the potential sites of regulation appear to be downstream ofthe asseme bly of the CD95 signaling complex reviewed in Ref 440 Events that occur later requiring d6 7mm gene expression and protein synthesis cannot rescue B cells longeterm from the irreversible effects of caspaseemediated DNA cleavage462 but can preserve cell viability until effector functions have been performed For example it has been shown that both BCR and CD40 signals enhance expression ofthe antiapoptotic protein bclexL and ectopic expression ofthis protein can inhibit CD957 mediated death454453 455 Another transcriptione ally regulated mechanism can operate through regue latory factors that downregulate CD95 expression466 Further study should reveal greater details about the multiple means B cells can use to regulate CD957 439 I r 39 anlfl39lPl OlCOf11 l391J C J death in control of Becell activation Volume 23 Number 3 V IMMUNOGLOBULIN ISOTYPE SWITCHING One of the most important components of the fully effective antibody response is the ability of B lymphocytes to change the class or isotype of Tg produced while retaining the antigenebinding specificity of the antibody The isotype of Tg molecules is contributed by their constant C region genes which endow each class ong with specialized properties allowing function to be tailored to be most effective in different situa tions TgM is an excellent isotype for an initial response because its pentameric structure perr mits greater clustering even if its affinity for antigen is not especially high However switched isotypes are designed for optimal function in subsequent stages of the humoral response For example TgG the most abundant serum Tg is highly effective at neutralizing bacterial and viral toxins whereas TgA binds to an additional come ponent that permits it to be transported across mucosal surfaces467 The presence of receptors for distinct Tg constant regions Fc receptors on varie ous cells of the immune system is another way in which distinct Tg isotypes perform specialized regue latory roles468 The severe clinical problems assoi ciated with defective isotype switching in HTGM patients discussed above demonstrate the impor tance of isotype switching in the effective defense against pathogens Most isotype switching involves cooperation between contactemediated TD signals and those delivered via lymphokine receptors with the type of lymphokine dictating the isotype prefe erence reviewed in Ref 469 H174 and 111713 preferentially stimulate switching to TgGlTgG4 and IgE7 W 472 interferoney to TgGZ473 and TL7 5 111710 or TGFe to TgA474 475 A key mechae nism by which lymphokines exert their effect on isotype selection appears to be the promotion of the production of the unrearranged germline transcript of the constant region gene for the selected isotype and TD signals enhance this eventfms 480 It is not yet clear how germline C gene transcription promotes isotype switching but a commonly held theory is that this transcrip tional activity leads to a more open chromosomal configuration7481 482 allowing greater accessibility of the DNA to recombinases that perform deletional switch recombination Prior to the realization that TD signals such as CD40 play an important role in normal isotype switching in wing systems successfully used bace terial products such as lipopolysaccharide LPS in combination with lymphokines to induce lg isotype switching 71476 This raises the possibility that perhaps any mitogenic stimulus could come bine with alymphokine signal to induce B cells to undergo isotype switching Indeed the process of isotype switching has been shown to be closely linked to regulation of Becell division483 485 However the severely defective isotype switch ing seen in HIGM patients who are regularly exposed to bacterial products suggests that ale though microbial stimuli may indeed induce some Tl isotype switching in viva TD signals predomie nate Of these CD40 provides a major signal to cooperate with lymphokines in inducing isotype switching in 39vi39va3 5 311 485 CD40 ligation can it self stimulate germline C gene transcription in addition to synergizing with lymphokine signals in this function487 and a distinct CD407respon7 sive transcriptional element has been identified in the germline C8 gene397 This particular role of CD40 appears to be mediated via its NFeKBi dependent pathway488 which may in part explain the isotype switching defect in p50 mice384 as well as the requirement for p65 in mediating switching to lgG3 489 Activation ofNFeKB medii ated by CD40 may cooperate with Stat67activated transcription induced by H174 receptor signale ing394 There is evidence that additional transcrip tion factors also play rolesquot90 493 including BASP which regulates both CD40 and H174 receptor signals393494 and Tibet which is required for normal production of lgGZa lgGZb and lgG3495 Other interactions involving TNFeR family receptors and ligands also participate in the regue lation oflg isotype switching Mice lacking TNF and lymphotoxineoc show defects in switching to lgG4 and lymphotoxin also appears to be ime portant in switching to lgE497 In addition to providing both lymphokine and contactemediated signals promoting isotype switching T cells can also provide signals that inhibit this process via CD307CD153 interactions as discussed above498 Interestingly the negative signal delivered by D30 may also target transcription of the germline 173 C region genes using a binding site distinct from those used by CD40 or H174 receptor signals499 Recently it has been shown that dendritic cells can also regulate isotype switching via the BAFF and APRIL molecules discussed above500 Although germline transcription and cell die vision are key components ofthe isotype switching process switching cannot occur without deletional recombination to juxtapose a new C region gene with the antigenebinding portion of the lg mole ecule The process of switch recombination is multifactorial and complex and has itself been the subject of many comprehensive reviews Thus for a more detailed discussion of switch recombinae tion the reader is referred to several recent ref views501 504 We summarize here the major steps in the process including recent information and unanswered questions It has become clear that two distinct processes are used in the recombination that generates VDJ recombination in lg genes and that which gene erates switch recombination VDJ joining does not require germline gene transcription505 and is dependent upon the activity of the recombinases RAGel and RACreZ o s 07 However class switch recombination CSR can still occur in RAG B cells508 In contrast isotype switching requires activity ofa cytidine deaminase AID activatione induced deaminase whereas VDJ recombinae tion does not509 lg C region genes are preceded by repetitive 1710 kb sequences unique to each C region called switch S regions and CSR occurs when an upstream S region undergoes none homologous recombination with that ofa down stream C gene deleting the intervening DNA503504 It is unclear what signals initiate CSR and the S region joining As mentioned above germline C gene transcription has been proposed to open chroe matin for access to recombinases but this transcrip tion may also have a more direct role in triggering recombination itself Because CSR involves nonhomologous joine ing of the S regions roles of various proteins involved in DNA break repair have been investi gated for potential participation in CSR The Ku subunits of DNA protein kinase are required for VDJ joining and their absence leads to a defect in production of switched lg isotypes510 511 This together with the findings that stimuli that prof mote isotype switching upregulate Ku exprese Critim Reviewxw in ImmumUgy sion and Ku may associate with CD40512513 indicate that Ku may play a role in CSR This conclusion is tempered however by the prolife eration defects found in KuedeficientB cells since cell division is also an important component of isotype switching It has also been found that mismatch repair enzymes are likely to play a role in CSR39502514515 A nding in recent years ofgreat interest was the discovery that a cytidine deaminase called AID is required for both class switching and lg somatic hypermutation see below in mice and humans515 517 Because AID also promotes mutae tion it is likely that this activity is key to its function an idea supported by the recent finding that AID can also mutate an actively transcribed gene expressed in a fibroblast cell line518 It ref mains to be discovered at which step of CSR AID is specifically required and its precise mode of action Another interesting protein recently implie cated in isotype switching is SWAP770 found in a screen of proteins that promote recombination in a cellefree model system SWAP770 like AID is induced upon switcheassociated stimuli and is expressed in locations where switched B cells are found519 Also like AID a deficiency in SWAP770 results in defective isotype switching but the effect is restricted to lgE520 How SWAP770 mediates its effects on switching to lgE is still an unsolved mystery it was recently discovered to associate with IF and promote guanine nucleotide exchange to Rac as well as localize to membrane i39uffles521 It appears likely that additional players in the isotype switch process await discovery VI BCELL MEMORY Antigen engagement ofB cells in viva can lead to a number of possible outcomes B cells actie vated by antigen and Tecell help can directly differentiate into lgMesecreting plasma cells or the B cells can enter the germinal center reace tion with those surviving ultimately emerging as either plasma cells or longelived memory cells reviewed in Refs 5227524 In the last few years several important findings concerning B memory cells have been published and are reviewed here Volume 23 Number 3 Memory B cells exhibit a number of distine guishing characteristics Because they have sure vived antigenedriven selection in the germinal center reaction they are characterized by point mutations in the antigenebinding portions of the BCR reviewed in Ref 525 They may have BCR of switched isotype although human memory B cells include a large population of lgMepositive memory cells526 Subpopulations ofhuman tonsile lar B cells have been defined using many surface markers including CD19 CD20CD38 and lgD and the memory B cells are identified as the population that is CD19CD20 CD383 and lgD 522 527 although there is a small population of lgM lgD cells that have undergone somatic hypermutation528 More recently CD27 has also been identified as a marker of human memory B cells528 529 The definition of these subsets has greatly facilitated the study of human memory B cells In contrast to the human system markers of mouse memory B cells are less welledefined Mouse germinal center cells are CD38 low PNAebinde ing high and GL7 high530v531 but CD38 is inf creased on memory cells and PNA binding def clines from the germinal center levels532 Mouse memory cell studies often use cells with switched isotype CD27 has not proven useful as a marker of mouse memory B cells Memory B cells appear to be optimized to respond positively to signals through the BCR Feldhahn et 31534 compared naive GC and memory subsets ofhuman B cells using serial analysis of gene expression reverse trane scriptaseePCR and flow cytometry They showed that mRNAs associated with BCR signaling inf cluding BLNK Btk lgoc lgB and Syk were increased in memory B cells compared to naive B cells533 Furthermore the mRNAs encoding inf hibitors of BCRemediated activationisHPe1 SHIP Csk and Cbliwere all higher in naive than in memory B cells533 The cytoplasmic tail oflgG also appears to confer a bursteenhance ing effect increasing the number of memory B cells and plasma cells produced in response to antigen534 Memory B cells express high levels of costimulatory molecules including CD19 CD21 CD27 CD40 CD74 CD80 and CD86 which 174 facilitate their interactions with T cells and accese sory cells528 533535 Memory B cells unlike germie nal center B cells express the adhesion receptors Leselectin 09437 and cutaneous lymphocyte antie gen536 They also can respond with chemotaxis to CXCL12 CXCL13 and CCL19 which allows a shift in the tissueespecific homing of memory B cells compared to naive B cells535 537 Cytokines appear to play an important role in directing the fate of memory B cells Arpin et al utilized an in vitm system to analyze the requirements for directing memory B cells to either proliferate or differentiate into antibodye secreting cells 538 These investigators showed that in the presence of cellebound CD154 the cytokines H172 and lLi10 would drive human GC cells to acquire a CD38 CD20 phenotype characteristic of memory cells and continue to proliferate while in the absence of CD154 or in the presence of blocking antibodies the cells would become CD38 CD20 plasma cells In this system 1L710 apparently acts by upe regulating expression of the higheaffinity H172 receptor539 a response that is greater in memory than naive B cells540 Interestingly another group has described a similar in vitm system in which treatment of human tonsillar GC cells with soluble CD154 in the presence of a follicular dendritic cell line gives rise to memory cells in the presence of H174 and H172 and plasma cells in the presence of lLe10 and 11172541542 Recone ciling the differences in response to lLe10 in the two systems may lie in closer analysis of the form and strength of the signal to the B cells through CD40 since variation in the CD40 signal has been suggested to affect the fate ofBecell differe entiation5quot3544 Memory B cells have higher levels of H174 receptors than their naive counterparts533 and treatment of memory B cells with H174 results in I cI ofa1zgt0 4 CI lin superfamily members which cooperate negae tively in signaling through the BCR533 Human memory B cells have elevated levels ofthe BAFF receptor BCMA as detected by flow cytometry as well as elevated levels of mRNAeencoding BAFFeR 33 The importance of BAFF in main taining the memory Becell population has not been explored 175 Although memory B cells appear to be poised to respond to specific antigen antigen is not ref quired for their maintenance5 l5546 Recent work from Lanzavecchia s group suggests that antigen specific memory B cells and antibody titers may rely on none speci c memory Becell stimulation from T cells stimulated in a noncognate fashion or by polyclonal activators They demonstrated that naive CD27 humanB cells do not proliferate well in response to unmethylated CpG DNA in vim even in the presence ofbystander Tecell help or to Tecell help alone unless first stimulated through the BCR547 In contrast memory CD27 B cells either lgM or of switched isotype responded robustly to CpG DNA or CpG DNA bystander Tecell help or to Ticell help alone without costimulation through the BCR resulting in both the proliferation of memory cells as well as their differentiation into plasma cells547 Furthermore lgD B cells of switched isotype isolated from human peripheral blood respond with greater proliferation to the polyclonal activator Stapb amrrm amem Cowan A strain H172 and Hr10548 Tollelike receptors TLR are involved in the innate immune response to a variety of microbial products The response of both mouse and hue man B cells to unmethylated CpG DNA is mediated by TLR9549550 Bernasconi et al have published RT7PCR data showing that naive hue man B cells do not express TLR9 unless first stimulated through the BCR whereas memory B cells express TLR9 constitutively as well as TLRs 6 7 and 10551 Two transcriptional repressor molecules have been postulated to hold the plasma cell terminal differentiation program in check BSAP encoded by the Pax5 gene and Bel6 reviewed in Ref 552 Most GC B cells are positive for the negative transcriptional regulatory protein Bcle which in J 4 models functions to inhibit the plasma cell differentiation program through blocking ex pression of Blimp1553 After leaving the GC memory cells appear to maintain a low level of expression of Bcle mRNA554 as well as Pax5 mRNA533551 but lack Blimp1555 Fearon et al 6 postulated that continued Bcle expression maintains the memory cells as a selferenewing population a stemecellyy for continual production of plasma cells It is not yet clear whether the levels of Bel6 and Pax5 Critim Reviewxw in ImmumUgy expression in memory cells is sufficient to prevent plasma cell differentiation or whether other mechae nisms may be required to maintain B cells in the memory cell stage VII CONCLUSIONS The topic ofantigenespecific Tedependent Becell activation covers a huge area ofresearch to which many investigators have and continue to contribe ute To preclude exorbitant length we have only been able to cover highlights of the current state of knowledge of the various steps in the process these are summarized in Figure 3 It is now abundantly clear that the ultimate outcome of the binding of antigen to the BCR is dependent upon the balance between a variety of regulatory signals delivered via coreceptors that send positive negative or both depending upon other factors messages to the cell The BCR itself utilizes lgeoc and lge to deliver activating signals These however are modulated by receptors such as CD19 CD21 CD22 and CD32 with the balance between Ag gt III Bcell BCR and friends lga lgB CD19 CD21 CD22 Antigen presentation TcellB cell interactions MHC II adhesion molecules these auxiliary signals determining how the B cell perceives the initial stimulus Experiments def scribed above have clearly demonstrated that a loss of any of these signaling pathways results in abe normal Becell responses to activating signals The ability ofthe B cell to process and present the antigen bound to its BCR allows it to engage in cognate interactions with an activated T cell This interaction results in the delivery of a large number of contactemediated signals between the two cells detailed in the preceding text and illuse trated in Fig 1 Many ofthese receptoriligand pairs have only recently been identified and more surely await discovery as does a more detailed understanding of the particular roles of each lnterestingly some of these receptors serve dual purposes in both signaling and additional funce tions eg adhesion molecules MHC class H and in some cases both receptor and ligand can also be found on activated B cells allowing further amplification of signals initially delivered by T cells see above The outcomes ofantigenespecific Tedepene dent Belymphocyte activation are also varied and each contributes to a fully functioning ime B cell effector functions Proliferation lg secretion Isotype switching Cytokine amp chemokine secretion Memow cell formation CD40 CD134 CD137L 0x40 CD27 CD70 CD30 CD153 BAFF AP RIL D95 Lymphokines chemokines FIGURE 3 Overview of antigenspecific Bcell activation Each of the steps and molecules involved is discussed in this review Activation is initiated by the binding of specific antigen to the BCR A variety of coreceptors serve to regulate the nature of the signal delivered by this binding Antigen is internalized processed and presented to the activated T lymphocyte and the interaction between T cell and B cell delivers numerous additional activating and regulatory signals to both cells The ultimate outcome ofthis complex process is Bcell effector functions which are summarized in the figure Volume 23 Number 3 mune system To be effective a specific clone of B cells must expand by proliferation to a size sufficient to counteract a microbial threat To interact effectively with T lymphocytes and ref ceive their many costimulatory signals the B cell must upregulate a number of surface molecules that enable it to be more effective in antigen presentation including adhesion molecules MHC molecules and costimulators such as CD80 CD81 CD27 and others The unique and most critical function of the r is t r i of antibar lie and thus full Becell activation must result in antibody production and secretion Additionally because particular immune responses optimally require distinct Ig isotypes the responding B cell must be capable of receiving and responding to signals specifying Igeisotype switching In cone cert with these processes B cells also serve as a source ofproduction ofa large variety oflymphoi kines and chemokines which serve to regulate the activity of B cells themselves and other cell types with which they interact As detailed above important cooperating signals in isotype switch ing development of memory and other Becell activation events are provided by soluble factors However a full discussion ofthe roles oflymphoi kines and c emokines in Becell activation is beyond the scope of this article The development of the humoral memory response although critical to normal mammalian health has long been mysterious and its mechae nisms elusive While the above discussion reveals that much remains to be understood considerable progress has been made in identifying memory B cells in the human and in understanding the signals and environmental cues required for the development of Becell memory Thus in all the events and stages of Becell activation many of the important details and requirements have been revealed over the past eca e However many questions remain to be answered In particular how each of the individual cues received by B cells are integrated to produce an effective welleregulated response is of great interest Emerging tools techniques and experie mental approaches will help to address these new areas of investigation I 177 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