浙江大学医学免疫学免疫1012T细胞.pptx

T cell and Cell-mediated immunityLu Linrong（鲁林荣）PhDLaboratory of Immune RegulationInstitute of ImmunologyZhejiang University，School of MedicineMedical Research Building B815-819Email:Lu.LWebsite:http:/ lymphocytea key player in the immune systemAbsence or hyperactivation of T cells leads to immunodeficiency,respectively chronic inflammation or autoimmune disorders.T CellBelongs to LymphocytesCan be distinguished by the expression of T cell receptor(TCR)Function:mediate cellular immunity;Thymus-derived lymphocyte:T cellOrigin:bone marrow stem cellDistributing:T Zone of secondary lymph node and peripheral blood(65-75%of total lymphocytes)1.Development of T cells2.T cell surface markers3.T cell subsets4.Functions of T cells5.Cell-mediated immunityOutline 1.Development of T cellsT cells develop in ThymusGeography of the thymus:Thymic epithelial cells control the maturation of thymocytesFactors promoting T cell development in the thymusnCytokines(IL-1,IL-6,IL-7)and hormones secreted by thymic stroma cells and thymocytes themselves.n Interaction of cell adhesion molecules between immature thymocytes and thymic stroma cellsThe nude mouse strain is athymic due to a mutation in the Foxn1nu gene that encodes FOXN1,a transcription factor of the forkhead box family.FOXN1 is preferentially expressed in the skin and thymus.Alteration of its expression in the thymus underlies the manifestation of severe immunodeficiency resulting from total absence of T cell development.The cortical epithelium of the thymus is critical for T cell developmentSequential development of thymocytesnPre-T cells:no T cell marker expressionnDouble negative cells(DN):CD4-CD8-;cytoplasmic CD3+nDouble positive cells(DP):CD4+CD8+,CD3+,TCRlow,TCRlow nMature T cells(single positive T cells):CD4+or CD8+,CD3+,TCR+Stages of T cell Stages of T cell development defined development defined by surface markersby surface markersStages of Thymocytes development in ThymusSurface marker for thymocyte developmentThe distinct stages of thymocytes can be identified by FACS analysis in respect to the expression of the CD4 and CD8 coreceptors.Percentages of the distinct cell populations are indicated in the respective quadrants(CD4 SP:upper left,DP:upper right,CD8 SP:lower right,DN:lower left).CD4CD8CD44CD25Surface marker for thymocyte developmentVDJ recombination and TCR expression is essential for Thymocytes developmentVDJ recombination and TCR expression is essential for Thymocytes developmentThymocytes development driven by stage-specific expression of Key moleculesPositive and negative selectionnPositive selection:DP cells that bind,with moderate affinity,to MHC-Ag on thymic stroma cells survive-MHC restrictionMHC I-CD8+T cellsMHC II-CD4+T cellsnNegative selection:Cells that bind to MHC-Ag on thymic stroma cells(or auto-reactive T cells,ART)with high affinity will undergo apoptosisFormation of central immune toleranceDownloaded from:StudentConsult(on 1 June 2006 01:58 PM)2005 Elsevier Positive and negative selection2.T cell surface markersCDs on T cellsCD3CD31.Consists of 5 proteins that are designated as,and.Three dimers:,()2.The cytoplasmic domain contains ITAM(immunoreceptor tyrosine-based activation motif)YxxL/V3.Function:transduction of signals that lead to T cell activation.CD4 and CD8CD4 and CD8transmembrane glycoproteintransmembrane glycoproteinco-receptor of T cellco-receptor of T cell*CD4:first and second domains bind to nonpolymorphic region of MHC moleculesCD8:IgV-like domain of chain binds to nonpolymorphic 3 region of MHCmolecules function:mediate adhesionfunction:mediate adhesion；mediate signal transmediate signal trans赌场提哦呢赌场提哦呢:lck:lck activationactivationfirst V-like domain of CD4 first V-like domain of CD4 -specific receptor of HIVspecific receptor of HIV APCCD28 and CD152CD28 and CD152(CTLA-4)(CTLA-4)CD28CD28+cellcell -all CD4-all CD4+T cell and 50%CD8 T cell and 50%CD8+T T cell;cell;CTLA-4CTLA-4+cellcell -activated T cell-activated T cellbinding to binding to B7-1(CD80)and B7-2(CD86)on the surface of B7-1(CD80)and B7-2(CD86)on the surface of APCAPC*CD28:provide an co-stimulatory signal for T cell *CTLA-4:suppress amplification of activated T cell (bring into play negative regulation）Interaction of CD28 with B7 provide 2nd signal for T cell activationCD40 and CD40L(CD154)CD40 and CD40L(CD154)ICOS:expressed on activated T cellsCD2:SRBC receptor,LFA-2 PD-1:ligand PD-L1,PD-L2LFA-1 and ICAM-1:mediate adhesion between APC(or target cells or endothelial cells)and T cells or other leukocytes.Other surface markersOther surface markersSummary of T cell surface markers3.T cell subsets 1 Naive T cells,effector T cells and memory T cells;2TCR T cells and TCR T cells;3CD4+T and CD8+T cells;4Th,Tc and TregT-cell responseNave vs memory T cells vs T cellsCD4 vs CD8 T cellsT cell differentiation4.Functions of T cells1.CD4+helper T cells(Th):Th0:Th cells that secrete broad spectrum of cytokines at low level.Th1:produce IL-2 and IFN-,but not IL-4.They are chiefly responsible for cell-mediated immune responses,but can also help B cells to produce IgG2a,but not much IgG1 or IgE;Th2:secrete IL-4,5,10,13,but not IL-2 and IFN-,are very efficient helper cells for production of antibody,especially of IgG1 and IgE;Th1 vs Th2CD4 T cell mediate immunity effecter functions 2.2.CD8CD8+cytotoxic T cells(CTL)cytotoxic T cells(CTL)Function:directly kill target cells(cytotoxicity)1.Cytolysis(necrosis)-three stages:a.contact phase:recognition of antigen in the context of MHC class I molecules b.secretory phase:release of cytolytic granules(perforin and granzymes)c.lysis phase:osmotic deathCTL Mechanisms 2.Cell apoptosis:a.FasL-Fas:CTLs express FasL interaction with Fas on target cells activation of caspase 8 apoptosisCTL MechanismsCTLTarget3.3.CD4CD4+CD25 CD25+regulatory T cells(Tr)regulatory T cells(Tr)Foxp3 positive Function:Down-regulation of immune response by inhibiting the activation and proliferation of CD4+or CD8+T cells.Mechanisms:Direct inhibition by contacting target cells.Inhibitory cytokines:IL-10,TGF-,et al.5.T cell-mediated immune response Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens,such as intracellular bacteria(mycobacteria,listeria monocytogens),viruses,protozoa,etc.Introduction3 Phases of T cell responsesuAntigen recognition phaseuActivation,proliferation and differentiation phaseuEffector phaseAntigen recognition Ag presentation by APCInteraction between Interaction between APC and T cellAPC and T cellNon specific binding of APC and TcellSpecific binding of APC and T cell TCR-peptide-MHC co-receptor-MHC co-stimulatory molecules T cell synapse or immunological synapse Ligand-receptor pairs involved in T cell activation AdhesionSignal transductionAntigen recognitionSignal transductionSignal transductionAdhesionActivation,proliferation and differentiation Activation,proliferation and differentiation The first signal:TCR-antigen peptide-MHC(double recognition)CD4-MHC II or CD8-MHC IThe second signal(co-stimulatory signal):Interactions between co-stimulatory molecules on APC and corresponding receptors on T cells CD28B7The third signal:Cytokines in T cell activation Two signals ensure T cell activationCo-stimulation provides signal IIself antigenOther requirements for T cell mediated response-Cytokine signal as signal III1.Synapse formation2.Activation of Src family PTK(p59fyn,p56lck)3.Phoisphorylation tyrosine of CD3 ITAM4.Recruitment and activation of Syk family PTK(ZAP-70)5.Phoisphorylation of adaptor LAT and SLP6.Activation of TF:NFAT,AP-1,NF-B,Oct-17.Transcription and expression of gene:IL-2 et al Signal transduction in T cell activation1,Formation of the Immunological SynapseWhen the TCR complex recognizes MHC-associated peptides on an APC,several T cell surface proteins and intracellular signaling molecules are rapidly mobilized to the site of T cell-APC contact.This region of physical contact between the T cell and the APC has been called the immunological synapse cSMAC:central supramolecular activation cluster (TCR/CD3,CD2,CD28,PKC q,lck)pSMAC:peripheral supramolecular activation cluster(LFA-1,Talin,CD43,CD45,CD148)2.Activation of Src family PTK(p59fyn,p56lck)3.Phoisphorylation tyrosine of CD3 ITAM4.Recruitment and activation of Syk family PTK(ZAP-70)5.Phoisphorylation of adaptor LAT and SLP6.Activation of signal pathways and TFs1)PLC-TCR-CD3ITAM ZAP-70LAT,SLP-76 PLC-IP3 Ca2+calcineurin NFAT PIP2 DAG PKC NF-B2)Ras-MAP ZAP-70phosphorylation of LAT and SLP-76Grb-2 and SosRasMAPKKMAPKAP-1Target genes activated by transcription factors CKs and their receptors CAMs MHCMajor signaling pathwaysMajor signaling pathways&Gene expression&Gene expressionDifferentiation of T cellsDifferentiation of T cells1)CD4+T cells:Th,Tr,Treg,Th17,Tm regulated by cytokines (signal 3)2)CD8+T cells:Tc Th-dependent Th-independent:virus infected DC that highly express co-stimulatory molecules can directly stimulate CD8+T cells.Differentiation of CD8 T cellsEffector functions of activated T cells1)CD4+T cells Th1:secrete IFN-,etc.express CD40L express FasL,kill Fas+target cells effect on lymphocytes:IL-2 effect on neutrophil:TNF-,Th2:promote B cell growth and Ig production mediate hypersensitivity Th17:IL-17,IL-8,TNF-:enhance leukocyte recruitment and inflammation Activate macrophagesActivation of macrophages by T lymphocytesEffector Effector functions of functions of CD4 T cells CD4 T cells Activation of Macrophage by Th1 cellsCytotoxicity:kill target cells a.necrosis:perforin and granzymeb.apoptosis:granzyme,FasLCharacteristics of CD8+T cell cytotoxicity a.Specificity b.MHC I restriction c.High efficiency2).Effector functions of CD8+T cells3)memory T cells 1)CD45RA-CD45RO+,2)Long-lived memory to specific antigen3)Mediate faster,stronger and more effective immune response 4)Mechanism:low dependent on costimulatory molecules or more sensitivity to cytokinesSummary1.Development of T cells:Markers and stages,Essentials;2.T cell surface markers:Related to Functions3.T cell subsets:vs;CD4 vs CD8;Ths.4.Functions of T cells:Th1,Th2,CTL;5.Cell-mediated immunity:Activation of T cells Effector of T cellsTHANK YOU FOR YOUR ATTENTION!SEE YOU NEXT TIME ON:IMMUNE TOLERANCE