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by: Mabelle Gusikowski
Mabelle Gusikowski
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Class Notes
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This 37 page Class Notes was uploaded by Mabelle Gusikowski on Wednesday September 9, 2015. The Class Notes belongs to HUBIO 523 at University of Washington taught by Staff in Fall. Since its upload, it has received 22 views. For similar materials see /class/192008/hubio-523-university-of-washington in Human Biology at University of Washington.


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Date Created: 09/09/15
T CellMediated Immunity Lectures 78 2008 Antigenindependent and Antigen dependent Stages of T Cell Development Selection by self antiqenMHC Activation by foreiqn antiqenMHC th mus Lymph Nodes and spleen CD4 gt A MHCquot Effector I HCy39 g Tcell i t to N v 3 AgMHCI i i l l l 539 gt ll DP SP Nai39ve Effector T cells T cells Dendritic Cells Are Highly Efficient APC That Carry Antigens from Tissues to Lymph Nodes Immature dendritic cells are antigen presenting cells resident in all tissues where they act as sentinels to detect microbes Dendritic cells take up microbes which stimulates them to leave quot the tissues migrating via lymphatics to local lymph nodes and to mature Mature dendritic cells home to T cell rich areas of the lymph nodes where they present antigens to T cells Figure 61 The Immune System 1 Garland Science 2005 Na39I39ve T cells Home to Secondary Lymphoid Tissues Looking for Foreign Antigens SP thymocytes gt naive T cells travel via blood to 2 lymphoid tissues Naive T cells that do NOT encounter specific foreign peptideMHC complexes in 2 lymphoid tissues gt recirculate life span years Naive T cells that DO encounter specific foreign antigenMHC complexes and costimulatory molecules on dendritic cells gt stay proliferate clonal amplification and differentiate into effector T cells Figure 53 The Immune System 2e e Garland Science 2005 Events and Molecules Involved in Na39l39ve T Cell Entry into Lymph Nodes Sega I ise39l ctii13 Figure 34 lmmunobiology 7ed 9 Garland Science 2008 Cell Adhesion Molecules and Chemokines Govern Na39I39ve T Cell Entry into Lymph Nodes Adhesion molecules allow T cells to bind to endothelial cells and to dendritic cells an important antigen presenting cell APC Selectins Lselectin on T cells binds to vascular addressins and mediate initial rolling interactions between T cells and vascular endothelium Integrins LFA1 and other integrins bind to ICAMs on endothelium these are firm interactions needed for migration across vascular endothelium and for subsequent T cell dendritic cell interactions Cell Adhesion Molecules and Chemokines Govern Na39I39ve T Cell Entry into Lymph Nodes Chemokines chemotactic cytokines Specific Chemokines in secondary lymphoid tissues attract naive T cells and allow them to bind firmly via integrins to specialized lymphoid endothelium HEV Specific Chemokines attract dendritic cells to secondary lymphoid tissues and attract T cells and dendritic cells to each other Cell Adhesion Molecules and Chemokines Govern Na39I39ve T Cell Entry into Lymph Nodes blood Lselectin lymph node Figure 66 The Immune System 2e Garland Science 2005 Animation T Cell Trafficking Adhesion Molecules and Chemokines Mediate Initial Interactions in Which T cells Search for Specific PeptideMHC on Dendritic Cells T cells initially bind dendritic cell through lowaffinity LFA1 lCAM1 Subsequent T cell activation by pepMHC Conformational change in LFA1 increases affinity and prolongs dendritic cell interactions s39gnals LFA391 cell cell contact T cell CD4 TCR LFA1 m rgt rgt quotI 1 MHC class II ICANH Figure 68 The Immune System 2e Garland Science 2005 Activation of Na39I39ve T Cells Requires 2 Signals Signal 1 results from TCRCD3CD4 or TCRCD3CD8 on the T cell engaging specific peptideMHC on the dendritic cell Signal 2 results from CD28 on the I 6 T cell engaging B7 a costimulatory 39 39 7 molecule also known as CD80 and CD86 on the dendritic cell Mature dendritic cells DCs have M high amounts of peptideMHC and ass B7 both of which are necessary to I I a I 3 activate naive T cells dend i e F gure 69 The Immune System2le Garland Science 2005 Microbial Ligands Induce Dendritic Cells and other APCs to Express More MHC and B7 T cells are highly specific but not intuitive they have no inherent ability to tell if an antigen is from a dangerous microbe or from one of our own cells they must be educated by dendritic cells and other antigen presenting cells APCs Dendritic cells and other APCs are inherently able to discern microbe from self because their pattern recognition receptors eg Tolllike receptors recognize microbe specific but not self structures and instruct the immature dendritic cell to mature gt to express much more peptideMHC and B7 Proliferation and differentiation of T cells specific for bacterial protein Figure 613 The immune System Zle Garland Science 2005 Three Types of Professional APCs Antigen presenting cells APCs are the only cells that constitutively express MHC class II with the exception of thymic cortical epithelial cells express greater amounts of MHC class I than other cell types can be induced to express B7 Mature dendritic cells are particularly efficient because they have more peptideMHC complexes and B7 than other APCs and they migrate preferentially to T cell zones in secondary lymphoid organs where they present peptideMHC to T cells l vira Tcell areas microbial toxin follicle antigen O virus infecting the dendritic cell l bacterium H V 39l Figure 6H The Immune System2E K Garland SKiE cE 2005 Dendritic Cells DCs Are the Most Efficient APCs and Are Essential for Antigen Presentation to Nai39ve T cells Immature DCs in tissues phagocytose bacteria fungi infected cells etc gt then process and present antigenic peptides from them on MHC and MHC II Interaction with microbes matures DCs gt DCs migrate from tissues to T cell zones in lymph nodes and other secondary lymphoid tissues increase MHC and II upregulate B7 costimulatory molecules Mature DCs attract naive T cells with chemokines Na39I39ve T cells are activated if DC has the specific peptide MHC recognized by their TCR Macrophages and B cells Are Also APCs Macrophages and B cells are APCs but generally have less peptideMHC and less B7 and thus are less efficient APCs than are mature DCs Thus macropages and B cells are NOT capable of inducing the activation of naive T cells but CAN induce activation of previously activated effectormemory T cells Macrophages present antigenic peptides from bacteria fungi and infected cells that they phagocytose B cells takeup antigens via surface lg ie they present peptides from the same antigens bound by their lg or that are physically associated with the antigens bound by their lg Na39I39ve T Cells Activated via Signal 1 2 Secrete lL2 Stimulating Them to Proliferate lowaffinity lL2 receptor MHC class II dendritic cell Figure as The Immune System 2e z Garland Science 2005 Figure 618 The Immune System2le 9 Garland Scienm 2005 T Cell Signaling as a Target for Clinical Immunosuppression Signal 1 via TCR gt Kinase Activation gt T Ca gt activate transcription factors l naiveTceu39 NFAT etc gt gt transcribe L2 L2 receptor or Cyclosporin A and tacrolimus block calciuminduced NFAT gt NO L2 gt NO proliferation Rapamycin blocks L2receptor mediated proliferation signals 0 Useful to block transplant I rejection but also impair immunity to infection and have other side effects dendritic cell Figure69 quot39L 39 V J Antigenindependent and Antigen dependent Stages of T Cell Development Selection by self antiqenMHC Activation by foreiqn antiqenMHC th mus Lymph Nodes and spleen CD4 gt A MHCquot Effector I HCy39 g Tcell i t to N v 3 AgMHCI i i l l l 539 gt ll DP SP Nai39ve Effector T cells T cells Nai39ve T cells Receiving Signal 12 are Activated But Signal 1 Alone Become Anergic 04 39g aii X Ti quotrivi7 ii3939quoti i classll V V Activates T cell T cell becomes anergic Figure 6 19 The Immune System 2le Garland Science 2005 T cells specific for microbial antigen are activated by mature DCs that display microbial peptideMHC plus B7 on their surface By contrast T cells specific for selfantigens become anergic permanently unresponsive upon interaction with selfpeptideMHC on immature DCs which lack B7 and soon die helping to rid the body of autoreactive T cells that escaped negativeselection in the thymus Activated Nai39ve T Cells Replicate and Differentiate into Effector and Memory T cells Proliferation of naive T cells leads to marked expansion doubling time 612hr clonal amplification Clonal T cell amplification from 1105396 gt 1103 gt10 in acute response to some viral pathogens Activated Nai39ve T Cells Replicate and Differentiate into Effector and Memory T cells Proliferation of naive T cells results in their differentiation into effector and memory T cells Compared to naive T cells effectormemory T cells have A lower activation threshold and are less dependent on costimulation by B7 Gained the ability to migrate to inflammedinfected tissues where effector function is needed Gained new functions and functional specialization CD4 helper Th cells CD8 cytotoxic T cells CTL Some provide immediate effector function and some differentiate into memory T cells that persist after the infection resolves gt long term protective immunity and immunological memory Properties and Functions of Effector T Cells Initial Response Effecmr Memory Protect Against Func on A Multicellular helminths worms J7 gt Extracellular bacteria fungi lFNJy Intracellular pathogens viruses CytotoxicIFNJy Intracellular bacteria and protozoans This updates the Parham book which was published before Th1 cells were identified Functional Specialization of Effector T cells Effector T cells produce potent mediators in response to activation by peptideMHC complexes Cytokines Iymphokines molecules that modify the functions of other cells Secreted interleukins eg L2 L4 L17 interferony IFNy and others Membrane anchored eg CD40 ligand tumor necrosis factor TNF Fas ligand Cytotoxins perforin granzyme that induce apoptosis of target cells Distinct functions of effector T cell subsets are determined by which cytokines and cytotoxins they produce CD8 Cytotoxic T cells Host Defense Against Viral and other Intracellular Intracytoplasmic Pathogens CD8 Effectors cytotoxic T lymphocytes CTL Lytic granules containing perforin and qranzvmes Surface apoptosisinducing molecule Fas ligand Kev cvtokine lFNv gt increases peptideMHC thereby increasing recognition by CD8 T cells Rapid and sequential induction of target cell death by apoptosis without necrosislysis CD8 CTL targets microbeinfected cells that have microbial peptideMHC class I complexes on their surface CD8 Cytotoxic T cells Focused Delivery of Cytotoxic Mediators to Limit Collateral Damage Collision and nonspecific adhesion Specific recognition redistributes cytoskeleton and cytoplasmic Release of lytic granules at site of cell contact 6 Movie CTL Killing CTL granule polarization and target cell apoptosis CTL red granules Target green elapsed time 5 min Stinchcombe Immunity 2001 15751 Cytotoxic CD8 T cells Are Selective Serial Killers Figure 629 The Immune System 2le Garland Science 2005 Animation CTL Killing Genetic Defects in Lytic Mechanisms Result in Lymphoproliferative Disorders FasFas Ligand dependent killing defect Autoimmune Lymphoproliferative Syndrome Type ALPS Defect in perforin or i 7 j r urea32 ThelmmuneSystemJewcarlandSclencezoos granuledependent killing mechanism Hemophagocytic Why Inability of CTL to kill per3istent infection lymphoproliferative leads to excessive of ineffective CTL producing Syndromes lots of IFNy gt excessive macrophage activation Th1 CD4 T Cells Cellular Immunity amp Host Defense to lntracelllular Intravesicular Pathogens Th1 T cells and cellular immunity defininq cvtokine lFNy also produce lL2 TNFoc and CD40 ligand IFNy CD40 ligand induce macrophage activation gt defense against intracellular pathogens ie bacteria and protozoans living within phagocytic vesicles increases antigen presentation by T MHC l and II Inhibit generation of Th1 and Th2 cells IFN y 39FN39V receptor J L Killing of intravesicular bacteria Figures 33 quot 39 ltydam 139 39 39 39 3mm Th17 CD4 T Cells Host Defense Against Extracellular Bacteria and Fungi TH17 cells Th17 T cells defininci cvtokine L17 also produce L21 L22 af afe and CD40 ligand L17 induces neutrophil broblasts production and entry into ep equotaquot quot infected tissues Defense against extracellular bacteria and fungi Inhibit generation of Th1 and Th2 cells VII1 neutrophils This updates the Parham book which was published before Th1 cells were identified Th2 CD4 T Cells Host Defense Against Intestinal Parasites worms Th2 T cells defininq cvtokine L4 also produce L5 L13 and CD40 ligand CD40 ligand and L4 induce B cells to produce lgE antibody L4 and IL 13 induce gutainNay mucus production and contraction lL5 induces eosinophils Defense against intestinal worms also mediate allergy Inhibit generation of Th1 and Th1 cells Kg 5 SglgE plasma cell eosinophils Individuals Who Mount a Th2 Rather Than Th1 Response to the Intravesicular Pathogen M Ieprae Develop Severe Lepromatous Leprosy There are two polar forms tuberculoid and lepromatous leprosy but several intermediate forms also exist Lepromatous leprosy F Tuberculoid leprosy Cytokine patterns in leprosy lesions V Tut cytokines TH2 cytokine s Tuberculoid Tuberculoid lL2 lL4 E l IE A organisms present a low to orgamsms Show growth Figmen TheImmuneSynlmillelcalnlndsdmmioail undetectable levels in macrophages Low infectivily High infectivity Granulomas and local inflammation Disseminated infection Peripheral nerve damage Bone cartilage and diffuse nerve damage Normal serum immunoglobulin levels Hypergammaglobulinemia Normal Tcell responsiveness Low or absent Tcell responsiveness Specific response to M Ieprae antigens No response to M Ieprae antigens Robust Th1 Robust Th2 CD4 Effector T Cells Help B Cells Some Th1 Th2 and Th1 effector CD4 T cells migrate to B cell follicles in response to chemokines made in the follicles Follicular B cells endocytose antigens via their surface g process and present peptideMHC II to the TCR of effector Th cells this is known as Cognate T cellB cell Interaction This interaction aided by the low levels of B7 present on B cells activates effector Th cells to express CD40 ligand cytokines CD40 ligand and cytokines bind to the B cells facilitating B cell activation proliferation g class switch from lgM to IgG in response to L21 andor IFNy or lgE in response to L4 and differentiation into longlived plasma cells and memory B cells This updates the Parham book which in several places depicts Th2 cells as the only cells that help B cells Regulatory Suppressor T Cells Regulatory T cells Tregs Inhibit DOS and inhibit activation of effector T cells Inhibition mediated by L10 TGFB CellCell Contact One important subset of Tregs is CD4CD25 Deficient in IPEX an X inked autoimmunity syndrome Key Points Na39ive T cells are relatively longlived cells that recirculate between blood and secondary lymphoid tissues until they encounter specific antigenMHC Entry into lymph nodes and subsequent interactions with dendritic cells and other APCs is mediated by cell adhesion molecules and chemokines APCs constitutively express MHC class II and class Mature dendritic cells DCs are the only APC that can induce the initial activation of nai39ve T cells because mature DCs express high amounts of peptideMHC providing signal 1 and B7 providing a costimulatory signal 2 to the na39ive T cells via engagement of TCRs and CD28 respectively In addition to DOS macrophages and B cells can act as APCs for previously activated effectormemory T cells Key Points Signal 1 signal 2 gt L2 and L2 receptor expression gt T cell activation signal 1 without signal 2 gt anergy unresponsiveness Activation gt clonal proliferation clonal selection and differentiation from rare antigenspecific na39ive T cells to abundant antigenspecific effector and memory T cells Effectormemory T cells have lower activation threshold new functions and can migrate to inflamed and infected tissues in addition to lymphoid tissues Effector CD4 T cells gt helper T cells Th act via cytokines and CD40 ligand Th1 cells interferonyCD4OL gt macrophage activation and cellular immunity and help B cells to make lgG antibodies thereby providing host defense against viruses and intracellular bacteria and protozoans Th1 cells produce L17 gt neutrophil recruitment and produce L21CD4OL gt help B cells to make lgG antibodies thereby providing host defense against extracellular bacteria and fungi Th2 cells produce L4CD4OL gt help B cells to make lgE antibodies L4 lL 13 gt mucus production lL5 gt eosinophils providing host defense against helminths and allergy Effector CD8 T cells gt cytotoxic T cells CTL induce death of infected cells and produce interferony providing host defense against viruses and some intracellular bacteria Some Th1 Th17 and Th2 cells and CD8 CTL become longlived memory T cells and mount a more effective response to subsequent infections


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