2 ObjectivesDescribe the protein-protein interactions necessary for naïve T cell activation to occurIllustrate or describe the changes that occur in a dendritic cell upon activationExplain the basic mechanisms through which cytotoxic T cells, TH1 cells, and TH2 cells functionBriefly describe the functions of regulatory T cellsPredict 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 cellsDendritic cellMacrophageB cell>
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
13 CostimulationCTLA4 is expressed on T cells after they become activatedSignaling through CTLA4 sends an “off signal” to the T cellCTLA4 knockout mice have been createdWhat would you expect the phenotype of these mice to be?
19 Cellular events triggered by activation Expression of high-affinity IL-2 receptor (CD25)Secretion of IL-2Proliferation (clonal expansion)Change in CAMs ( L-selectin)Differentiation into armed effector T cellsNo costimulation required
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 cellsTH1 cells suppress differentiation of TH2 cells, and vice versa
32 Regulatory T cellsRegulatory T cells suppress the activity of other classes of T cellsEvidence for multiple subsets of regulatory T cellsCD4+/CD25+ T cellsTR1TH3Regulatory CD8+ cellsSome secrete IL-10 and/or TGF-Some require contact with other T cells to have effectsAntigen-specific or “bystander” suppression
33 Regulatory T cells can suppress inflammation Inflamed colon in mouse model of colonic inflammationSame mouse model given CD4+ CD25+ regulatory T cells by IV transferRead, Malmstrom, & Powrie. Journal of Experimental Medicine 192: , 2000.
34 Discussion questionsWhat effect on T cell-mediated immunity would each have?A blocking antibody to IL-2 or to the high-affinity IL-2 receptorA 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