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Date Created: 09/09/15
The Development of T lymphocytes T cells Lecture 6 2008 What Have You Learned with Alan Overview of the innate and adaptive immune responses B lymphocytes immunoglobulin lg and antibodies ie secreted lg lg molecules are generated by VDJ recombination after which negativeselection removes most B cells 5 with autoreactive lg In response to foreign antigen mature B cells further 39vmph idp39 gequot 39 diversify V regions via somatic hypermutation improving lg affinity and may switch C regions from lgM to lgG lgA or lgE modifying lg function T lymphocytes T cell receptors TCRs are generated by VDJ recombination Unlike lg TCRs do NOT undergo somatic hypermutation or class switching TCRs bind to antigenic peptideMHC complexes Today T cell precursors how they develop Into mature T cells Overview I Precursors migraTe from The bone marrow via The blood To The Thymus T cell developmenT occurs in The Thymus a primary lymphoid organ T ThymusdependenT bone marrow Figure 51 The Immune System 2e Garland Szience 2005 Overview II Thymic epi rhelium expresses MHC class I and MHC class II and grow rh fac rors each of which is necessary for T cell developmen r and survival Thymocy res imma rure in rra rhymic T cell precursors Ma rure T cells migra re via The blood To The secondary lymphoid organs Lymph nodes Spleen Guiassocia red lymphoid rissues GALTMALT Ll llfl L W T I iquot gt73 4 a U 2539 A 1 CF U a Me U a b 3 ll Ulich ll NR Ellllb ng U li Ll L lt5 ll 39 L39 r i r39V39 quotN C vc rquot r U M Will U U gfiEU DiGeorge syndrome chromosomal microdele rion gt developmen ral defec rs of hear r para rhyroid and Thymus T cell deficiency of varying degree if sev 39 The Thymus is Required for Tcell Mo39rur39o39rion DiGeor39ge syndrome chromosomal micr39odele rlon gt developmen rol defec rs of heor39T por39o rhyr39oid and Thymus T cell deficiency of vor39yin degree If severe gt clinically monifes r Immunode Iciency Thymic developmen r comple re in humans by midges ro rion 20 weeks Thymus slowly bu r pr39or39essively involu res durjmg oodul r llfe bu r cell numbers mom rolned because T cells are longlived Major Stages of T Cell Development From Common Lymphoid Precursors As They Occur in the Thymus 7 2ofDN become SP Common Lymphoid Precursor Cell t Thymocyte E SP Stage CD4CD8 CD4CD8 CD4CD8 double double single negative positive positive Major Stages of T Cell Development Are Defined by Surface Expression of CD4 CD8 and TCRICD3 Earliest progenitors are CD4CD8 doublenegative DN and are also TCR and CD3 negative TCR rearrangement success determines which of two major lineages a T cell adopts VS few or 043 most TCR and CD3 are always coexpressed If TCR then CD3 CD3 is a complex of invariant proteins that transduce signals from the TCR to the interior of the cell TCRocB thymocytes mature through a CD4CD8 double positive DP stage then to CD4 or CD8 SP stage Stages and Checkpoints of T Cell Development in the Thymus QSta e E SP Early Stages of Intrathymic T Cell Development VDJ rearrangement commences in DN thymocytes at the TCR y8 and B loci lnframe productive rearrangement of TCR VS before 3 gt y8TCRCD3 gt emigrate from thymus as 35 T cell nonMHC restricted function in preadaptiveinnate like immunity Productive rearrangement of TCR 3 before 35 gt TCRBpreTocCD3 gt proliferate and express CD4ampCD8 preToc analogous to the surrogate light in preB cells Failed rearrangement gt die Intermediate Developmental Stages of TCRoc lineage Thymocytes preTocTCRBCD3 thymocytes proliferate clonal amplification analogous to that occuring in early preB cells with productive lgH rearrangements Then stop proliferating become CD4 and CD8 DP and initiate TCRoc rearrangement Productive TCRoc rearrangement gt CD4CD8TCRocl3CD3 DP thymocytes V V D J C 5 IH1HH Germllne gene V V J C configuration a v39 L7 V V V DJ J C 3 3I ii D J 39 rearrangement a V V J c I Figure 56 part 1 of 3 The Immune System2le Garland Science 2005 V5 DJB stops cell proliferates CD4CDB induction a transcription starts rearrangement V V in frame at chain protein produced 5 V g E E g v39 I7 Surface expression V oi 3 chain with VDJ J C surrogateachain mi W V 3 rearrangement v V J c Figure 5 6 part 2 of3 The Immune System2le 6 Garland Science 2005 Vol I J01 rearrangement surface expression V J J C of 6003 a A V selectioncan now begin Figure 56 part 3 of 3 The Immune System2le Garland Science 2005 Selection tests for TCR interaction with selfpeptideMHC Positive and Negative Selection Allows Only Potentially Useful aBT Cells to Mature to SP Stage Development into CD4 vs CD8 T Cell ls Determined by the MHC class on which the Cells TCR is Positive Positive selection terminates further TCRoc gene rearrangement DP thymocytes positively selected on MHC class I lose CD4 retain CD8 coreceptor gt CD8 SP thymocytes amp T cells DP thymocytes positively selected on MHC class II retain CD4 coreceptor gt CD4 SP thymocytes amp T cells 7519 u um Receptor bins selfpeptideseIfMHC class i lySelected eceptor bins 39 39 quot Inun nlnee ll CD4 C08 T cell CD4 T cell Figure 512 The Immune System 22 6 Garland Science 2005 Bare Lymphocyte Syndromes Genetic T CellCombined Immunodeficiency with markedly reduced MHC Expression MHC class II deficiency gt impairs positive selection numbers and function of CD4 T cells TAP deficiency failure of peptide loading and cell surface expression of MHC class I gt impairs positive selection numbers and function of CD8 T cells T Cells Are Restricted to the MHC Allotype on Which They Were Positively Selected Positive selection the T cell is selected for its ability to interact weakly with the MHC molecules of the allotvpes present on thvmic epithelial cells lhymic epithelial cell The TCR is now restricted to can only recognition of foreign antigenspeptides on MHC molecules of the SAME allotype MHC restriction CD8 T cells are restricted to recognition of peptides bound to MHC class I molecules of the same allotypes CD4 T cells are restricted to recognition of peptides bound on MHC class II molecules of the same allotypes Implications of Positive Selection for Bone MarrowStem Cell Transplantation Treatment for leukemia bone marrow failure genetic immunodeficiencies Leukemia is treated with intensive radiation and chemotherapy killing off recipient bone marrow and bone marrowderived cells including most T and B cells Bone marrow stem cells of donor are infused and over weeks replace recipient marrow stem cells and all bone marrowderived cells including T and B cells but do not replace other cells including thvmic epithelial cells l Figure S10 The Immune System 2e Garland Science 2005 Implications of Positive Selection Donor and recipient must be matched for at least one MHC class I and one MHC class II allotype Necessary so T cells derived from donor stem cells which will be gositivelv selected on and restricted to recoqnition of antiqen on MHC allotvpes of recipient thvmic epithelial cells can recognize foreign antigens on at least one MHC and one MHC II allotype ofthe antiqen presentinq cells derived from donor marrow 7 7 Problem solved I j 7 selectedlon reoipienl and some donor J 512m ri i r lja39yzau b39al 1 leis Ease 1 the i1 arlm39agr sm 1 Circulating T cell siare Antigenpresenting restricted by recipienl colls39in 39 and some donor antigens o ns ome HLA allowpes Funlimit HI A Illnhl ni upon infection same Aquot agamive immune response is made that terminates t e lu patifogende riiled antigens Upon lnfectlon to cells can respond to pa cyanderived antigens presented Donor derived thyme cyj 39s are posithiely selected on recipient 39 LA allotyp Circulating T cells are restricted by reb39i pi n t hilt not donor HLA allotypes Antigenpresenting cells ingti39s39su s present antigens on donorHLA allotypes Na adaptive immime responseis madevand i the infection persist APCs 1 it o Positive and negative selection are mediated by different types of cell in the thymus region Immature CD3394 839 Cortical doublenegative thymocyls epithelial cell mediates positive cortex A selection Immature CD348 doublepositive thymocytes Dendrmc cortico cell mediates medullary negative junction L selection Mature curequot and CD398 medullary thymocytes gt epithelial medulla 0 cell Q venule macrophage 0 Figure 513 The Immune System2le Garland Science 2005 Negative Selection Removes Dangerous T Cells Negative selection eliminates strongly autoreactive and potentially dangerous T cells is mediated by APCs dendritic cells gtgt thymic stromal cells only removes T cells strongly reactive with self MHC MHC of that individual s allotypes removes T cells strongly reactive with self peptideMHC only when the self peptides are present in the thymus Aire autoimmune regulator protein allows thymic epithelial cells to make small amounts of many proteins normally found only in other tissues thereby leading to negative selection of T cells reactive to these antigens rare people with mutations in Aire develop an autoimmune disease called APECED APECED fingernails Overview T Cell Development tianto doub Wm IDa lhymocyles posi ive E IHI39Y Inthe sub Junction capsular zone CD3 hymocytes Dunble pusilive Positive CD3 thymocyles seleclicln in the lhymil conex Doublepositive cm thymucyles Negative seleuion and especlally all he curlica medullary junction Malqu sellrestrictedv elftolerant singlepusilive CD4 or CDS T m Enlry to the clrculmlon cans leave quotIE Ihymus in blood venules Figure 518 The Immune System2le Garland Science 2005 T Cell Leukemia and Lymphoma Like B cell malignancies may occur as a result of aberrant DNA rearrangement Clonal malignant population based on uniform T cell receptor rearrangement NL Clonal Germline unrearranged aquot 39 C151 gene a Common T cell acute lymphoblastic leukemia ALL derived from immature thymocytes Other T cell malignancies derived from later CD4 or S zary syndrome CD8 stages of development leukemia Mycosis fungoides T cell Chronic lymphocytic leukemia CLL T prolymphocytic quot leukemia T PLL Acute lymphoblastic thymocyte leukemia TALL 6397 CD3TCR CD4 or CD8 Key Points T cells derive from bone marrow stem cells that differentiate in the thymus T thymus dependenD In the thymus each T cell generates a unique T cell receptor TCR by gene rearrangement TCR is composed of yes few or of most T cells that fail to make a TCR die T cells with dB TCRs dBT cells undergo positive and negative selection in the thymus Key Points Selection of ocBT cells in the thymus Positive selection T cell precursors with TCR that interact weakly with selfpeptideMHC complexes survive and mature these have the potential to recognize foreign peptideself MHC complexes strongly and to protect against infection Negative selection eliminates T cell precursors with TCR that interact strongly to selfpeptideMHC complexes these could cause selfinjury if not eliminated Mature T cells are restricted to recognition of peptides bound to selfMHC Positive selection on MHC class I gt CD8 T cells Positive selection on MHC class II gt CD4 T cells
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