T lymphocytes play a central role in cellular and humoral immune responses, carrying out direct effector functions such as cytolysis as well as mediating regulatory functions via secreted lymphokines. While the TCR accounts for the specificity of T cell responses, other T cell surface molecules also influence T cell responses. Some T cell surface structures correlate with the class of MHC antigen which restricts their responses: CD8+ """"""""cytolytic"""""""" T cells are restricted by class I MHC antigens while CD4+ 'helper' T cells are restricted by class II MHC antigens. CD4+ T cells have been subdivided further on the basis of the array of secreted lymphokines: T(H)1 cells secrete IL-2 and IFN-gamma but not IL-4 or IL-5 while T(H)2 cells secrete IL-4 and IL-5 but not IL-2 or IFN-gamma. This distinction also correlates with functional differences between these subsets: T(H)l calls mediate delayed-type hypersensitivity while T(H)2 cells efficiently 'help' B cells responses. These CD4+ T cell subsets also respond differently to immunoregulatory processes: IFN-gamma inhibits the proliferation of T(H)2 clones, but not of T(H)l clones. T(H)1 cells pretreated with IL-2 do not respond when stimulated subsequently through the TCR; proliferation of T(H)2 cells is enhanced by IL-2 pre--treatment. Treatment of T(H)l clones with high concentrations of anti-TCR mAb inhibits IL-2-induced proliferation; this treatment augments proliferation of T(H)2 clones. Signalling pathways also differ; stimulation of the TCR induces an increase in intracellular (Ca2+) in T(H)l but not in T(H)2 clones. The general goal of this research proposal is to characterize further some of the regulatory processes that control differentially the functions of murine CD4+ T lymphocyte subsets. There are four Specific Aims: 1) To determine the biochemical basis for the differences in signal transduction observed in murine T(H)1 and T(H)2 clones; 2) To determine the basis for the selective stimulation of proliferation of T(H)l cells by splenic adherent cells (AC) and of T(H)2 cells by B cells; 3) To identify other possible selective influences that favor activation and expansion of T(H)1, T(H)2, and other murine T cell subsets; and 4) To develop mAb which can distinguish between murine T(H)l and T(H)2 T call subsets. The proposed studies should provide insights into the regulatory processes that control T cell growth and function.
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