Chapter 4 T Cell Mediated Immune Response（CMI）

T Cell Mediated Immune Response（CMI） Chapter 4 T Cell Mediated Immune Response（CMI） Contents PartⅠ General introduction PartⅡ T cells mediated immune response PartⅢ NKT cell and δT cell mediated immune response PartⅣ Unspecific activation of T cells

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

1. Conception of immune response Broad sense of immune response: Unspecific immune response (innate immunity) barrier structure immunocytes: NK, Mф, DC, B1, γδT immune molecules: C, CK, lysozymes Specific immune response (adaptive immunity) T cell mediated immune response B cell mediated immune response

Prevention from Infection

1. Conception of immune response Narrow 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

Capture and presentation of exogenous Ags 被膜 输出淋巴管 Capture and presentation of exogenous Ags tissue Lymphatic vessel DC antigen Afferent cortex Lymph node

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, infection By mediating cells T cell mediated immune response---CMI B cell mediated immune response---HI

PartⅡ 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 order to be recognised by T cells Soluble native Ag Cell surface native Ag Soluble peptides of Ag Cell surface peptides of Ag Cell surface peptides of Ag presented by cells that express MHC molecules APC ANTIGEN PROCESSING No T cell response No T cell response No T cell response No T cell response T cell response

The process of T-cell mediated Immune response 1.T cells recognize the Ag peptide-MHC complex on APC ------MHC restriction 2. Activation, proliferation and differentiation of T cells ------Dual signals 3.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 Ⅱ 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-αhelix, CDR3 recognizes Ag peptide. MHC restriction

Three dimensional structure of TCR

Anatomical mechanism of TCR recognizes MHC/antigenic peptide MHC-a helix TCR-b chain CDR1 CDR2 Antigenic peptide CDR3 CDR3 CDR2 CDR1 TCR-a chain MHC-a helix

CDR3 CDR2,1 CDR1,2

T cell synapse(突触) a special structure between T and APC T 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 signals First signal：specific antigen signal TCR — peptide-class Ⅱ MHC complexes CD4 — class Ⅱ MHC molecule(β2) Second signal：co-stimulatory signal CD28 — B7（CD80、CD86） CD2（LFA-2）— CD58（LFA-3） LFA-1 — ICAM-1

TCR complex

The Two-Signal Hypothesis Co-stimulatory signal (CD28/B7)

2. Activation, proliferation and differentiation of CD4+T cell (1) Activation: dual signals First signal：specific antigen singal TCR — peptide-class Ⅱ MHC complexes CD4 — class Ⅱ MHC molecule(β2) Second signal：co-stimulatory signal CD28 — B7（CD80、CD86） CD2（LFA-2）— CD58（LFA-3） LFA-1 — ICAM-1 VLA-4 — VCAM-1

2 1

Molecules associated with T activation CD4 MHC-II TCR/CD3 1 ICAM-1 B7-1 B7-2 LFA-1 ICAM-3 LFA-3 CD28 CD2 2 Molecules associated with T activation Th cell APC CTLA-4 —

Dual signal model of Th cell activation APC block Th activity Dual signal model of Th cell activation IL-2R Th Signal 1 Signal 2 LPS TNF-a IL-1 IL-6 IL-2 Th activated CD28 B7 CD28

（2）proliferation：CKs—IL-2 Resting 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.

Proliferation of T cell Tm Effector T

（3）Differentiation： Daughter cells differentiate into effector T cells and some differentiate into memory T cells (basis of vaccine). Th1(IL-2、IFN-γ、TNF-β） Thp Th0 Th2（IL-4、5、6、10、13） IL-12 Ag IL- 4 IL-23 （IL-6，TGF-β） Th17（IL-17）

Easily triggered by low antigen 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

Principle of T cell mediated immune response Immunological memory Days after immunity Ratio of specific T cells in blood 感应阶段 Primary immunity Secondary immunity 1/10000 1/1000 1/100 0 7 14 21 28 35 42 Principle of T cell mediated immune response

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

（Th1，Tc）

(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 pathogens Promote Th1 activation Mediate delayed hypersensitivity

(2) The functions of Th2 cells Th2 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 ⅠMHC complex on APC -------MHC restriction (1) Endogenous antigens----APCs (2) Ag recognition: TCR on T cells bind with Ag peptide-classⅠMHC complexes on APCs specifically. Dual recognition: CDR1, CDR2 recognize MHC-αhelix, CDR3 recognizes Ag peptide. MHC restriction

Interaction between TCR and homocysteine presented by HLA-A68 TCR-a chain TCR-b chain Homocysteine C Peptide HLA-A68 b2m

2. CD8+T cell Activation, proliferation and differentiation (1) Activation: dual signal First signal：specific antigen signal TCR — peptide-class Ⅰ MHC CD8 — class Ⅰ MHC Second signal：co-stimulatory signal？ CD28 — B7（CD80,CD86） CD2（LFA-2）— CD58（LFA-3） LFA-1 — ICAM-1

APC Signal 1 Signal 2 ?

Dual signal model of Tc activation block activity Dual signal model of Tc activation IL-2 Target cell activate, expansion Th Tc APC tumor Tumor cell CD28 DC B7 CD28 B7 CD28

Activation of CD8+T cell Virus 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

（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).

3．Function of effector CTLs CTLp recognized peptide-class Ⅰ 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.

（1）The process of CTL killing target cells Specific recognition and binding of target cell by CTL Lethal hit to target cell Lysis or apoptosis of target cell

① ② ③

（2）Characteristics of CTL killing target cells： Specific killing ClassⅠMHC molecule restriction Continuous killing of target cells in short time, and no injury of CTL

No injury Normal cell No injury

（3）Mechanism of CTL killing target cell: Perforin -- osmotic lysis Granzyme and Fas/FasL -- apoptosis Secreted TNF and IFN- induce target cells to die *Fas：Apo-1 or CD95

Cell death TNF and IFN- (minor pathway)

CTL cell Target cell

Biological effect of CMI 1. 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 Ⅳ hypersensitivity.  

Part Ⅲ NKT cell and δT cell mediated immune response

1. Ir mediated by NKT cell NKT cell: T cell which express molecules of NK cells Recognize lipid Ag presented by CD1 molecule Activated NKT cells secrete IFN-  and IL-4

NKTcells

2. Ir mediated by T cell CD4- and CD8- T cell Antigens: bacteria, virus Not need APC No MHC restriction

PartⅣ Unspecific activation of T cells Superantigen Unspecific activation Need APC, but not processing and presenting Secrete CK

The mechanism of superantigen activating T cell TCRVb Superantigen(sAg) Antigenic peptide Class II MHC a chain APC

Ag and SAg Antigen Superantigen

The other activators of T cells mitogen(PHA, ConA) anti-CD3, anti-TCRαβ, anti-TCRγδ anti-CD28