Chapter 14 T Cell Mediated Immune ResponseCMI

Contents Part General introduction Part T cells mediated immune response Part NKT cell and T cell mediated immune responsePart Unspecific activation of T cellsChapter 14 T Cell Mediated Immune ResponseCMI

Part Introduction Conception of immune response Stages of immune response Sites of Immune response Types of immune response

1. Conception of immune responseBroad sense of immune response:Unspecific immune response (innate immunity) barrier structure immunocytes: NK, M, DC, B1, T immune molecules: C, CK, lysozymesSpecific immune response (adaptive immunity) T cell mediated immune response B cell mediated immune response

Prevention from Infection

1. Conception of immune responseNarrow sense of immune response:specific immune response (Adaptive immunity)

Definition: a process that ICC recognize the antigens specifically, then activate (or lose their ability to be activated), proliferate, differentiate and play immunological effect.

2. Stages of Immune response

(1) Induction stage: Ag processing, presentation and recognition.(2) Reaction stage: activation, proliferation and differentiation of ICC (dual signals, CKs).(3)Effect stage: play immunological effect (CK, CTL, Ab).

3. Sites of Immune response----peripheral immune organs Lymph node, Spleen, MALT

4. Types of adaptive immune response

By 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 T cell mediated immune response---CMI B cell mediated immune response---HI

Part Cellular immunity T cell mediated immune response (CMI) CD4+T cell mediated immune response

CD8+T cell mediated immune response

Antigens must be processed in orderto be recognised by T cells T cellresponseNo T cellresponseNo T cellresponseNo T cellresponseNo T cellresponseANTIGENPROCESSINGAPC

The process of T-cell mediated Immune response1.T cells recognize the Ag peptide-MHC complex on APC ------MHC restriction2. Activation, proliferation and differentiation of T cells ------Dual signals3.The functions of effector T cells ------Th cell and CTL (Tc cell)

CD4+T cell mediated immune response

1. 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 recognizes Ag peptide.MHC restriction

Three dimensional structure of TCR

Anatomical mechanism of TCR recognizes MHC/antigenic peptideMHC-a helixAntigenic peptideCDR1CDR2CDR3CDR3CDR2CDR1TCR-b chainTCR-a chainMHC-a helix

CDR3CDR2,1CDR1,2

T cell synapsea special structure between T and APCT cell synapse can be called immunological 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.

2. Activation, proliferation and differentiation of CD4+T cell

(1) Activation: dual signalsFirst signalspecific antigen signal TCR peptide-class MHC complexes CD4 class MHC molecule(2)Second signalco-stimulatory signal CD28 B7CD80CD86 CD2LFA-2 CD58LFA-3 LFA-1 ICAM-1

TCR complex

The Two-Signal HypothesisCo-stimulatory signal(CD28/B7)

2. Activation, proliferation and differentiation of CD4+T cell

(1) Activation: dual signalsFirst signalspecific antigen singal TCR peptide-class MHC complexes CD4 class MHC molecule(2)Second signalco-stimulatory signal CD28 B7CD80CD86 CD2LFA-2 CD58LFA-3 LFA-1 ICAM-1 VLA-4 VCAM-1

12

CD28CD28B7

2proliferationCKsIL-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 daughter cells under IL-2 by autocrine or paracrine.

TmEffector TProliferation of T cell

3DifferentiationDaughter cells differentiate into effector T cells and some differentiate into memory T cells (basis of vaccine). Th1(IL-2IFN-TNF-Thp Th0 Th2IL-4561013IL-12 IL- 4AgIL-23IL-6TGF-Th17IL-17

characteristic of 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 memory

Immunological memory

3. The functions of effector Th cells

3. The functions of effector Th cells

Th1 Th2 CKs IL-2 ++++ IL-4 ++++ IL-5 ++++ IL-10 +++ IFN- ++++ TNF- +++ CKs for proliferation IL-2 IL-2/IL-4 Helping IgG,DTH IgE/IgA Inhibition Th2 Th1

Th1Tc

(1) The functions of Th1 cells Th1 cells release IFN- to activate macrophage, mediate inflammatory reaction and inhibit the function of Th2 cells. Th1 cells release IL-2 to promote the proliferation, differentiation of Th1 cells and Tc cells.

Effect of macrophage:Phagosize and kill pathogensPromote Th1 activationMediate delayed hypersensitivity

(2) The functions of Th2 cellsTh2 cells release IL-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.

CD8+T cell mediated immune response

1.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: CDR1, CDR2 recognize MHC-helix, CDR3 recognizes Ag peptide.MHC restriction

b2mTCR-b chainTCR-a chain Homocysteine HLA-A68PeptideInteraction between TCR and homocysteine presented by HLA-A68 C

2. CD8+T cell Activation, proliferation and differentiation

(1) Activation: dual signalFirst signalspecific antigen signal TCR peptide-class MHC CD8 class MHCSecond signalco-stimulatory signal CD28 B7CD80,CD86 CD2LFA-2 CD58LFA-3 LFA-1 ICAM-1

Signal 1Signal 2 ?APC

Tumor celltumorDCCD28CD28B7B7CD28

Activation of CD8+T cellVirus infected DCs activate CD8+T cell directly

Help of CD4+Th cell to CD8+T cell: Secreted IL-2 acts as the second signal Enhance expression of co-stimulator on APC

2Activated Tc cells proliferate and produce a lot of daughter cells under IL-2. 3Daughter cells differentiate into effector CTL and some differentiate into memory Tc cells(basis of vaccine).

3Function of effector CTLsCTLp recognized peptide-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.

1The process of CTL killing target cellsSpecific recognition and binding of target cell by CTLLethal hit to target cell Lysis or apoptosis of target cell

2Characteristics of CTL killing target cells Specific killingClassMHC molecule restrictionContinuous killing of target cells in short time, and no injury of CTL

Normal cell No injury No injury

3Mechanism of CTL killing target cell:Perforin -- osmotic lysisGranzyme and Fas/FasL -- apoptosisSecreted TNF and IFN- induce target cells to die

*FasApo-1 or CD95

Cell death TNF and IFN- (minor pathway)

CTL cellTarget cell

Biological effect of CMI1. Play an important role in defense agaist intracellular microbe infection.2. Kill tumor cells or virus-infected cells. 3. Participate in graft rejection and graft-versus-host disease(GVHD).4. Mediate type hypersensitivity.

Part NKT cell and T cell mediated immune response

1. Ir mediated by NKT cellNKT cell: T cell which express molecules of NK cellsRecognize lipid Ag presented by CD1 moleculeActivated NKT cells secrete IFN- and IL-4

NKTcells

2. Ir mediated by T cellCD4- and CD8- T cellAntigens: bacteria, virusNot need APC No MHC restriction

Part Unspecific activation of T cellsSuperantigenUnspecific activationNeed APC, but not processing and presentingSecrete CK

Superantigen(sAg) TCRVbAntigenic peptideClass II MHC a chainT cellAPCThe mechanism of superantigen activating T cell

Ag and SAg

The other activators of T cells

mitogen(PHA, ConA)anti-CD3, anti-TCR, anti-TCR anti-CD28