1. Chapter 4 T Cell Mediated Immune Response（CMI）

2. 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

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 that ICC recognize the antigens specifically, then activate (or lose their ability to be activated), proliferate, differentiate and 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被膜
输出淋巴管
Capture and presentation of exogenous Ags
tissue
Lymphatic vessel DC
antigen
Afferent
cortex
Lymph node

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 T cell mediated immune response (CMI)
CD4+T cell mediated immune response CD8+T cell mediated immune response

12. 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

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(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.

23. 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

25. TCR complex

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

28. 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

29. 2 1

30. 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 —

32. 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

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 cellTm
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. 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

42. 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
Principle of T cell mediated immune response

44. 3. The functions of effector Th cells

45. 3. The functions of effector Th cells

46. Th Th2
CKs
IL —
IL —
IL —
IL —
IFN- —
TNF- —
CKs for proliferation IL IL-2/IL-4
Helping IgG,DTH IgE/IgA
Inhibition Th Th1

47. （Th1，Tc）

51. (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.

52. Effect of macrophage: Phagosize and kill pathogens
Promote Th1 activation
Mediate delayed hypersensitivity

56. (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.

59. CD8+T cell mediated immune response

60. 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

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

64. 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

65. APC
Signal 1
Signal 2 ?

66. 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

68. 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

69. （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).

71. 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.

72. （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

74. ① ② ③

75. （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

77. No injury
Normal cell
No injury

78. （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

80. Cell death TNF and IFN- (minor pathway)

81. CTL cell
Target cell

88. 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.  

89. Part Ⅲ NKT cell and δT cell mediated immune response

90. 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

91. NKTcells

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

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

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

96. Ag and SAg
Antigen
Superantigen

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