Jianzhong Chen, Ph.D.Institute of Immunology, ZJU

Concept of immune responseT cell-mediated immune responseB cell-mediated immune response

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.

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.

Types of intracellular microbes combated by T cell-mediated immunity

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.

Three phasesAntigen recognition phaseActivation and differentiation phaseEffector phase

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)

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

Ligand-receptor pairs involved in T cell activation

Important properties of the major accessory molecules

The role of costimulation in T cell activation (A)

The role of costimulation in T cell activation (B)

Anergic T cell

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.

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

Signal transduction pathways in T cell activation

PIP2

gene expression of T cell

cytokine gene expression cytokine receptor gene expression adhesion molecule gene expression MHC

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.

Activation of CD8+ T cells

• 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.

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

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

Function of Th2 CD4 ＋ T cell

Regulate Mφ(recruitment, inhibition ： IL-10/FasL/TGF-)

B cell activation, Ig isotype switching

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

Two types of cell-mediated immunity

Cell-mediated immunity against intracellular microbes

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

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

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

Two mechanisms of lymphocyte apoptosis

Activation induced cell death Passive cell death

proliferation

Persistent stimulation

Deprived of growth factors

mitochondria

cytochrome C