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

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

Three phases Antigen recognition phase Activation and differentiation phase Effector 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-  IP 3 → Ca 2+  → calcineurin → NFAT → PIP 2 { 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

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 CD40LFasL 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

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 granzyme b. apoptosis: granzyme, FasL Characteristics of CD8 + T cell cytotoxicity a. Specificity b. MHC I restriction c. High efficiency 2) CD8 + T cells

Downloaded from: StudentConsult (on 1 June :50 PM) © 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 antigen ： TD-Ag antigen ： TD-Ag cell ： T cell and APC cell ： T cell and APC effect agent ： Th/CTL （ Tc ） effect agent ： Th/CTL （ Tc ） immune effects: anti-intracellular infection immune effects: anti-intracellular infection anti-tumor anti-tumor immunological injury immunological injury delayed type hypersencitivity, DTH delayed type hypersencitivity, DTH graft exclusion reaction graft exclusion reaction autoimmune disease autoimmune disease

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

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 deathPassive cell death proliferation Persistent stimulation Deprived of growth factors mitochondria cytochrome C