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T cell-mediated immunity Chapter 8

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Presentation on theme: "T cell-mediated immunity Chapter 8"— Presentation transcript:

1 T cell-mediated immunity Chapter 8

2 Objectives Describe the protein-protein interactions necessary for naïve T cell activation to occur Illustrate or describe the changes that occur in a dendritic cell upon activation Explain the basic mechanisms through which cytotoxic T cells, TH1 cells, and TH2 cells function Briefly describe the functions of regulatory T cells Predict appropriate target molecules for suppression of T cell function

3 T cell-mediated immunity
Mature naïve T cell (non self-reactive, MHC-restricted) Activation (stimulated by binding to specific antigen presented by APC) Clonal expansion and differentiation into armed effector T cells (CTL, TH1, TH2)

4 Antigen presentation is required for T cell activation
“Professional” APCs are highly effective at activating mature naïve T cells Dendritic cell Macrophage B cell >

5 Professional APCs

6 MHCII Lysosomal protein

7 T cells that become activated remain in the lymph node

8 T cell activation occurs in peripheral lymphoid tissues
Mature naïve T cells leave the blood and enter the T-cell zone of lymph nodes (or peripheral lymphoid tissues) Mediated by protein-protein interactions between the T cell and the endothelial cell

9 T cell : APC interactions

10 Naïve T cells require two signals for activation

11 Costimulation

12 Costimulation

13 Costimulation CTLA4 is expressed on T cells after they become activated Signaling through CTLA4 sends an “off signal” to the T cell CTLA4 knockout mice have been created What would you expect the phenotype of these mice to be?

14 Costimulation requirement helps prevent autoimmune responses

15 Activated APCs express costimulatory molecules
Pathogens activate APCs by inducing high expression of costimulatory molecules TLR signaling

16 B7 and MHC II expression on splenic dendritic cells from mice injected with LPS
Control (ip PBS) ip LPS iv LPS # cells B7 # cells MHCII

17 Adjuvants induce costimulatory molecule expression on APCs

18

19 Cellular events triggered by activation
Expression of high-affinity IL-2 receptor (CD25) Secretion of IL-2 Proliferation (clonal expansion) Change in CAMs ( L-selectin) Differentiation into armed effector T cells No costimulation required

20 Armed effector T cells

21 Armed effector T cells form stable interactions with target cells

22 Effector molecules produced by T cell subsets

23

24 Cytotoxic T lymphocytes (CTL, TC, CD8+ T cells)

25 Cytotoxic T lymphocytes

26 Cytotoxic T lymphocytes
Cytotoxic T lymphocytes express cytotoxins: Perforin forms pores in target cell membranes Granzymes are proteases that cleave caspase-3 Also express Fas ligand, IFN-, TNF

27 Cytotoxic T lymphocytes
Effects of CTLs are highly specific

28 TH1 cells

29 TH1 cells

30 Granulomas form when intracellular pathogens are not eliminated

31 What determines whether helper T cells become TH1 or TH2 cells?
Cytokines expressed by APCs and phagocytes determines differentiation fate of helper T cells TH1 cells suppress differentiation of TH2 cells, and vice versa

32 Regulatory T cells Regulatory T cells suppress the activity of other classes of T cells Evidence for multiple subsets of regulatory T cells CD4+/CD25+ T cells TR1 TH3 Regulatory CD8+ cells Some secrete IL-10 and/or TGF- Some require contact with other T cells to have effects Antigen-specific or “bystander” suppression

33 Regulatory T cells can suppress inflammation
Inflamed colon in mouse model of colonic inflammation Same mouse model given CD4+ CD25+ regulatory T cells by IV transfer Read, Malmstrom, & Powrie. Journal of Experimental Medicine 192: , 2000.

34 Discussion questions What effect on T cell-mediated immunity would each have? A blocking antibody to IL-2 or to the high-affinity IL-2 receptor A blocking antibody to TNF- Soluble CTLA-4 (mimics CTLA-4 activity) A blocking antibody to IFN- Collecting naïve T cells from a patient, stimulating them to become antigen-specific CTL against a tumor antigen, and injecting back into the patient


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