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
Activation (stimulated by binding to specific antigen presented by APC) Clonal expansion and differentiation into armed effector T cells (CTL, TH1, TH2) T cell-mediated immunity Mature naïve T cell (non self-reactive, MHC-restricted)
B cell > > Macrophage Dendritic cell Antigen presentation is required for T cell activation • “Professional” APCs are highly effective at activating mature naïve T cells
MHCII Lysosomal protein
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
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?
Activated APCs express costimulatory molecules • Pathogens activate APCs by inducing high expression of costimulatory molecules • TLR signaling
Control (ip PBS) ip LPS iv LPS B7 and MHC II expression on splenic dendritic cells from mice injected with LPS # cells B7 # cells MHCII
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
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
Cytotoxic T lymphocytes • Effects of CTLs are highly specific
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
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
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 192:295-302, 2000.
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