1. Cellular Immune response
Weilin Chen, Ph.D.
Institute of Immunology, ZJU

2. Concept of adaptive immune response
T cell-mediated adaptive immune response
B cell-mediated adaptive immune response

3. I. Concept of immune response
A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.

4. II. T cell-mediated immune response
Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.

5. Types of intracellular microbes combated by T cell-mediated immunity

6. 1. Phases of T cell responses
The response of T cells to antigens consist of a series of sequential steps that result in an increase in the number of antigen-specific T cells and the conversion of naïve T cells to effector T cells.

7. Three phases Antigen recognition phase
Activation and differentiation phase
Effector phase

9. 2. Antigen recognition
1) Substances that induce T cell activation
antigen (presented by APC)
Superantigen
mitogen (PHA, ConA, etc.)
mAb (anti-T cell surface molecules)

10. 2) Double signals for T cell activation
The first signal
TCR-antigen peptide-MHC (double recognition)
CD4-MHC II or CD8-MHC I
The second signal (co-stimulatory signal)
Interactions between co-stimulatory molecules on APC and corresponding receptors on T cells
CD28/CTLA-4 —B7, LFA-1—ICAM-1,
LFA-2—LFA-3

11. Ligand-receptor pairs involved in T cell activation

12. Important properties of the major accessory molecules

13. The role of costimulation in T cell activation (A)

14. The role of costimulation in T cell activation (B)
Anergic T cell
The role of costimulation in T cell activation (B)

15. 3. Signal transduction in T cell activation
On recognition of Ag and costimulators, T cells express proteins that are involved in proliferation, differentiation and effector functions of the cells.
The biochemical pathways that link Ag recognition with T cell responses consist of the activation of the enzymes, recruitment of adapter proteins, and production of active transcription factors.

16. There two major signaling pathways
1) PLC- TCR-CD3→ITAM → ZAP-70→LAT, SLP-76→ PLC- IP3 → Ca2+ →calcineurin → NFAT →PIP2{ DAG→ PKC → NF-B 2) MAPK ZAP-70→phosphorylation of LAT and SLP-76→Grb-2 and Sos→Ras→MAPKK→MAPK→AP-1 Target genes activated by transcription factors CKs and their receptors CAMs MHC

17. Signal transduction pathways in T cell activation
PIP2
Signal transduction pathways in T cell activation

18. gene expression of T cell
cytokine gene expression
cytokine receptor gene expression
adhesion molecule gene expression
MHC

19. 4. Proliferation and differentiation of T cells
1) CD4+ T cells: Th, Tr, Tm regulated by cytokines 2) CD8+ T cells: Tc Th-dependent Th-independent: virus infected DC that highly express co-stimulatory molecules can directly stimulate CD8+ T cells.

20. Activation of CD8+ T cells

21. Cytokines are required in T cell proliferation and differentiation
Activated T cells can produce cytokines (IL-2, 4, 7, 10, etc.) and express cytokine receptors, that promote T cells to proliferate and differentiate.

22. 5. Effector functions of activated T cells
1) CD4+ T cells Th1: secrete IFN-, etc. express CD40L express FasL, kill Fas+ target cells effect on lymphocytes: IL-2 effect on neutrophil: TNF-, Th2: promote B cell growth and Ig production mediate hypersensitivity
Activate macrophages

23. Biological roles of Th1 cell secreted cytokines
activated Th1 cell
IFN-γand CD40L
FasL or TGF-β
Lumen of blood vessel
exudation
chemoattractive
Infected site
activate Mφ to kill phagocyted bacterias
kill infected cell and released bacterias were killed by Mφ
induce T cell proliferation
induce differentiation of bone marrow Mφ
Induce Mφexudation by endothelial cell activation
recruitment of Mφto local infected site
Biological roles of Th1 cell secreted cytokines

24. Function of Th2 CD4＋T cell
Regulate Mφ(recruitment, inhibition：IL-10/FasL/TGF-)
B cell activation, Ig isotype switching

25. Function of Th17 CD4＋T cell
Secret：IL-17/IL-22/IL-21
Inflammation，infection disease，autoimmune disease

26. Function of Tfh CD4＋T cell
IL-21；CD40L，ICOS
B cell activation, Ig isotype switching

27. 2) CD8+ T cells Cytotoxicity: kill target cells
a. necrosis: perforin and granzyme
b. apoptosis: granzyme, FasL
Characteristics of CD8+ T cell cytotoxicity
a. Specificity
b. MHC I restriction
c. High efficiency

28. Mechanisms of killing of infected cells by CD8+ CTLs
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© 2005 Elsevier

29. Two types of cell-mediated immunity

30. Cell-mediated immunity against intracellular microbes

32. T cell mediated immune response and immune effects
antigen： TD-Ag
cell： T cell and APC
effect agent： Th/CTL（Tc）
immune effects: anti-intracellular infection
anti-tumor
immunological injury
delayed type hypersencitivity, DTH
graft exclusion reaction
autoimmune disease

33. 6. Generation of memory T cells
1) CD45RA-CD45RO+, 2) Long-lived memory to specific antigen 3) Mediate faster, stronger and more effective immune response 4) Mechanism: remains elusive

34. 7. Activation induced cell death, AICD
1) Activation induced cell death Activated T cells express FasL that induce apoptosis of Fas positive T cells. 2) Passive cell apoptosis Ag, survival signals and growth factors 

35. Activation induced cell death Passive cell death
proliferation
Persistent stimulation
Deprived of growth factors
mitochondria
cytochrome C
Two mechanisms of lymphocyte apoptosis