医学免疫学英文教学课件：Chapter14 T cell mediated immune response(8)

1、1Chapter14 T Cell Mediated Immune Response（CMI）2Contents Part General introduction Part T cell mediated immune response Part NKT cell and T cell mediated immune responsePart Unspecific activation of T cells3Part Introduction Conception of immune response Stages of immune response Sites of Immune res

2、ponse Types of immune response 4Broad sense of immune response:Innate immunity: barrier structures immunocytes: NK, Mo/M, Neutrophil, DC, B1, T, NKT immune molecules: C, CK, lysozymesAdaptive immunity: T cell mediated immune response B cell mediated immune response1. Conception of immune response5Pr

3、evention from Infection6Features of adaptive immunitySpecificMemoryAcquiredTransferableSelf-restriction-TCR, BCR-memory cells-Ag dependent-products of IR-immune regulation71. Conception of immune responseNarrow sense of immune response:Adaptive immunityDefinition: a process that ICC recognize the an

4、tigens specifically, then activate (or lose their ability to be activated), proliferate, differentiate and play immunological effects.ICC: immunocompetent cell(antigen specific lymphocytes) 8 2. Stages of Immune responseInduction stage: Ag processing, presentation and recognition.(2) Reaction stage:

5、 Activation, proliferation and differentiation of ICC (dual signal, CK).(3)Effect stage: Play immunological effects (CK, CTL, Ab).93. Sites of Immune response-peripheral immune organs Lymph node, Spleen, MALTBT10被膜输出淋巴管Capture and presentation of exogenous Ags tissueLymphatic vesselDC antigenAfferen

6、t lymphatic vessel cortexLymph node 11Lymphocyte recirculation124. Types of adaptive immune responseBy consequence Positive Ir: Normal Ir-anti-tumor, anti-infection Abnormal Ir-hypersensitivity, autoimmunity Negative Ir: Normal Ir-self immune tolerance Abnormal Ir-tumor, infectionBy mediating cells

7、T cell mediated immune response-CMI B cell mediated immune response-HI13Part Cellular immunity T cell mediated immune response (CMI) CD4+T cell mediated immune response CD8+T cell mediated immune response14Antigens must be processed in orderto be recognised by T cellsYT T cellresponseCell surfacepep

8、tidesof AgNo T cellresponseNo T cellresponseNo T cellresponseNo T cellresponseSolublenative AgCell surfacenative AgSoluble peptidesof AgCell surface peptides of Ag presented by cells that express MHC moleculesANTIGENPROCESSINGAPC15The process of T-cell mediated Immune response1.T cells recognize the

9、 Ag peptide-MHC complex on APC -MHC restriction2. Activation, proliferation and differentiation of T cells -Dual signals, CK3.The functions of effector T cells -Th cell and CTL (Tc cell)16CD4+T cell mediated immune response171. CD4+T cells recognize the Ag peptide-class MHC complex on APCs-MHC restr

10、iction(1) Exogenous antigens-APCs 18191. CD4+T cells recognize the Ag peptide-class MHC complex on APCs-MHC restriction(1) Exogenous antigens-APCs (2) Ag recognition: TCR on T cells bind with Ag peptide-MHC complexes on APCs specifically.Dual recognition: CDR1, CDR2 recognize MHC-helix, CDR3 recogni

11、zes Ag peptide.20Three dimensional structure of TCR21Anatomical mechanism of TCR recognizes MHC/antigenic peptideMHC-a helixAntigenic peptideCDR1CDR2CDR3CDR3CDR2CDR1TCR-b chainTCR-a chainMHC-a helix22CDR3CDR2,1CDR1,2231. CD4+T cells recognize the Ag peptide-class MHC complex on APCs-MHC restriction(

12、1) Exogenous antigens-APCs (2) Ag recognition: TCR on T cells bind with Ag peptide-MHC complexes on APCs specifically.Dual recognition: CDR1, CDR2 recognize MHC-helix, CDR3 recognizes Ag peptide.MHC restriction242526T cell synapsea special structure between T and APCT cell synapse can be called immu

13、nological synapse. When TCR complex recognizes peptides/MHC on APC, several T cell surface proteins and intracellular signaling molecules (such as CD3,CD4,CD8,CD28) are rapidly mobilized to the site of T cell-APC contact.27 2. Activation, proliferation and differentiation of CD4+T cell (1) Activatio

14、n: dual signalFirst signal：specific antigen singal TCR complex peptide-class MHC complexes CD4 class MHC molecule(2)28TCR complex2930The Two-Signal HypothesisCo-stimulatory signal(CD28/B7)3132 2. Activation, proliferation and differentiation of CD4+T cell (1) Activation: dual signalFirst signal：spec

15、ific antigen singal TCR peptide-class MHC complexes CD4 class MHC molecule(2)Second signal：co-stimulatory signal CD28 B7（CD80，CD86） 331234 2. Activation, proliferation and differentiation of CD4+T cell (1) Activation: dual signalFirst signal：specific antigen singal TCR peptide-class MHC complexes CD

16、4 class MHC molecule(2)Second signal：co-stimulatory signal CD28 B7（CD80，CD86） CD2（LFA-2） CD58（LFA-3） LFA-1 ICAM-1 VLA-4 VCAM-135CD4MHC-IITCR/CD31ICAM-1B7-1B7-2LFA-1LFA-1ICAM-3LFA-3B7-1CD28CD28LFA-1ICAM-3CD22Molecules associated with T activation Th cellAPCCTLA-43637APCblock Th activityDual signal mo

17、del of Th cell activationIL-2RAPCThSignal 1Signal 2LPSTNF-a IL-1 IL-6IL-2ThSignal 1Th activatedCD28CD28B738394041（2）proliferation：CKsIL-2Resting T cells express low affinity IL-2R.Activated T cells express high affinity IL-2R and secrete CKs such as IL-2.T cells proliferate and produce a lot of daug

18、hter cells under IL-2 by autocrine or paracrine.4243TmEffector TProliferation of T cell44（3）Differentiation：Daughter cells differentiate into effector T cells and some differentiate into memory T cells (basis of vaccine). Th1(IL-2,IFN-,TNF-）Thp Th0 Th2（IL-4,5,6,10,13）IL-12 IL- 4Ag45 Characteristic o

19、f memory T Cells (Tm): Long lived cells CD45RA-,CD45RO+ Easily triggered by low antigen Less dependent on co-stimulatory molecules Sensitive to CKs Responsible for maintaining immunological memory4647Days after immunityRatio of specific T cells in blood感应阶段Primary immunitySecondary immunity1/100001/

20、10001/1000 7 14 21 28 35 42 Principle of T cell mediated immune response Immunological memory48493. The functions of effector Th cells 503. The functions of effector Th cells 51（Th1，Tc）52535455(1) The functions of Th1 cells Th1 cells release IFN- to activate macrophage, mediate inflammatory reaction

21、 and inhibit the function of Th2 cells. Th1 cells release IL-2 to promote the proliferation, differentiation of Th1 cells and Tc cells.56The effects of macrophage:Phagosize and kill pathogensAmplify Th1 responseMediate delayed hypersensitivity57585960(2) The functions of Th2 cellsTh2 cells release I

22、L-4, 5, 6, 10 to activate the B cells to produce Ab.Th2 cells release IL-4, 5 to promote the differentiation and development of eosinophil and mast cell.Th2 cells release IL-10 to inhibit the activation of macrophage and function of Th1 cells. 6162Th9,Th17, Th22, TregMore than two decades ago, we vi

23、ewed helper T cells as having two major fates, Th1 and Th2 cells. But now we recognize the new diversity of helper T cells including Th17, Th9, Th22, Tfh and different types of regulatory T cells. 64Th17: CD4+IL-17Treg: CD4+CD25+Foxp3+65 CD8+T cell mediated immune response661.CD8+T cells recognize A

24、g peptide-class MHC complex on APC-MHC restriction(1) Endogenous antigens-APCs 67681.CD8+T cells recognize Ag peptide-class MHC complex on APC-MHC restriction(1) Endogenous antigens-APCs (2) Ag recognition: TCR on T cells bind with Ag peptide-classMHC complexes on APCs specifically.Dual recognition:

25、 CDR1, CDR2 recognize MHC-helix, CDR3 recognizes Ag peptide.69b2mTCR-b chainTCR-a chain Homocysteine HLA-A68PeptideInteraction between TCR and homocysteine presented by HLA-A68 C701.CD8+T cells recognize Ag peptide-class MHC complex on APC-MHC restriction(1) Endogenous antigens-APCs (2) Ag recogniti

26、on: TCR on T cells bind with Ag peptide-classMHC complexes on APCs specifically.Dual recognition: CDR1, CDR2 recognize MHC-helix, CDR3 recognizes Ag peptide.MHC restriction7172 2. CD8+T cell Activation, proliferation and differentiation (1) Activation: dual signalFirst signal：specific antigen signal

27、 TCR peptide-class MHC CD8 class MHC73Signal 1Signal 2 ?APC74 2. CD8+T cell Activation, proliferation and differentiation (1) Activation: dual signalFirst signal：specific antigen signal TCR peptide-class MHC CD8 class MHCSecond signal：co-stimulatory signal？ CD28 B7（CD80,CD86） CD2（LFA-2） CD58（LFA-3）

28、LFA-1 ICAM-175 block activityDual signal model of Tc activationIL-2Target cell activate, expansionThTcAPC TcTumor celltumorDCCD28CD28B7B7CD287677Activation of CD8+T cellDCs infected virus activate CD8+T cell directly Help of CD4+Th cell to CD8+T cell: Secreted IL-2 acts as the second signal Enhance

29、expression of co-stimulator on APC78（2）Activated Tc cells proliferate and produce a lot of daughter cells under IL-2. （3）Daughter cells differentiate into effector CTL and some differentiate into memory Tc cells(basis of vaccine).79CTLCTLTarget cell803Function of effector CTLsCTLp recognize peptide-

30、class MHC proliferate and differentiate to effector CTL under action of IL-2 released by Th1.The effector CTLs specifically recognize and bind Ag on target cells.CTL releases perforin, granzymes and express Fas ligand to kill target cells. 81（1）The process of CTL killing target cellsSpecific recogni

31、tion and binding of target cell by CTL.Lethal hit to target cell. Lysis or apoptosis of target cell.828384（2）Characteristics of CTL killing target cells： Specific killing.ClassMHC molecule restriction.Continuous killing of target cells in short time, and no injury of CTL.8586Normal cell Normal cell

32、is intact No injury87（3）Mechanism of CTL killing target cell:Perforin - osmotic lysis.Granzyme and Fas/FasL apoptosis.Secreted TNF and IFN- induce target cells to die.8889 Cell death TNF and IFN- (minor pathway)90CTL cellTarget cell91929394959697Biological effects of CMI1. Play an important role in defense against intracellular microbe infection.2.Kill tumor cells