jianzhong chen, ph.d. institute of immunology, zju
TRANSCRIPT
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Jianzhong Chen, Ph.D.Institute of Immunology, ZJU
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Concept of immune responseT cell-mediated immune responseB cell-mediated immune response
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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.
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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.
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Types of intracellular microbes combated by T cell-mediated immunity
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1. Phases of T cell responsesThe 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.
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Three phasesAntigen recognition phaseActivation and differentiation phaseEffector phase
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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)
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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
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Ligand-receptor pairs involved in T cell activation
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Important properties of the major accessory molecules
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The role of costimulation in T cell activation (A)
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The role of costimulation in T cell activation (B)
Anergic T cell
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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.
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There two major signaling pathways
1) PLC- TCR-CD3→ITAM → ZAP-70→LAT, SLP-76→ PLC- IP3 → Ca2+ →calcineurin → NFAT
→PIP2{ DAG→ PKC → NF-B2) 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
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Signal transduction pathways in T cell activation
PIP2
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gene expression of T cell
cytokine gene expression cytokine receptor gene expression adhesion molecule gene expression MHC
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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.
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Activation of CD8+ T cells
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• 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.
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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
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Biological roles of Th1 cell secreted cytokines
activated Th1 cell
IFN-γand CD40L FasL or TGF-β
Lumen of blood vessel
exudationchemoattractive
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
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Function of Th2 CD4 + T cell
Regulate Mφ(recruitment, inhibition : IL-10/FasL/TGF-)
B cell activation, Ig isotype switching
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Cytotoxicity: kill target cells a. necrosis: perforin and granzymeb. apoptosis: granzyme, FasL
Characteristics of CD8+ T cell cytotoxicity a. Specificity b. MHC I restriction c. High efficiency
2) CD8+ T cells
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© 2005 Elsevier
Mechanisms of killing of infected cells by CD8+ CTLs
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Two types of cell-mediated immunity
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Cell-mediated immunity against intracellular microbes
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T cell mediated immune response and immune effects
• antigenantigen : : TD-AgTD-Ag• cellcell : : T cell and APCT cell and APC• effect agenteffect agent : : Th/CTLTh/CTL (( TcTc ))• immune effects: immune effects: anti-anti-intracellular infectionintracellular infection
anti-tumoranti-tumor immunological injuryimmunological injury
delayed type hypersencitivity, DTHdelayed type hypersencitivity, DTH graft exclusion reactiongraft exclusion reaction
autoimmune diseaseautoimmune disease
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6. Generation of memory T cells
1) CD45RA-CD45RO+, 2) Long-lived memory to specific
antigen3) Mediate faster, stronger and
more effective immune response 4) Mechanism: remains elusive
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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
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Two mechanisms of lymphocyte apoptosis
Activation induced cell death Passive cell death
proliferation
Persistent stimulation
Deprived of growth factors
mitochondria
cytochrome C
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