Chapter 14 T Cell Mediated Immune Response （ CMI ）

1. Chapter 14 T Cell Mediated Immune Response（CMI）

2. Contents Chapter 14 T Cell Mediated Immune Response（CMI） • PartⅠ General introduction • PartⅡ T cells mediated immune response • PartⅢ NKT cell and δT cell mediated immune response • PartⅣ Unspecific activation of T cells

3. PartⅠ Introduction • Conception of immune response • Stages of immune response • Sites of Immune response • Types of immune response

4. 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

5. Prevention from Infection

6. 1. Conception of immune response Narrow sense of immune response: specific immune response (Adaptive immunity) Definition: a process thatICC recognize the antigens specifically,then activate (or lose their ability to be activated), proliferate, differentiateand play immunological effect.

7. 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).

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

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

10. 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

11. PartⅡ Cellular immunity Tcell mediated immune response (CMI) CD4+T cell mediated immune response CD8+T cell mediated immune response

12. T Y Cell surface peptides of Ag presented by cells that express MHC molecules Soluble native Ag Soluble peptides of Ag Cell surface peptides of Ag Cell surface native Ag Antigens must be processed in order to be recognised by T cells APC ANTIGEN PROCESSING T cell response No T cell response No T cell response No T cell response No T cell response

13. 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)

14. CD4+T cell mediated immune response

15. 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

17. Three dimensional structure of TCR

18. 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

19. CDR3 CDR2,1 CDR1,2

22. T cell synapse • 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.

23. 2. Activation, proliferation and differentiationofCD4+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

25. TCR complex

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

28. 2. Activation, proliferation and differentiationofCD4+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

29. 2 1

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

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

36. （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.

38. Proliferation of T cell Tm Effector T

39. （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）

40. 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

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

44. 3. The functions of effector Th cells

45. 3. The functions of effector Th cells

46. 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

47. （Th1，Tc）