Although the specificity of a T cell immune response is dictated by the TCR, the interaction of cytokines with their receptors is required for the clonal expansion and differentiation of antigen-activated T cell into effector cells, for limiting the magnitude of the response, and for maintaining the homeostasis of naive and memory peripheral T cells. Some of the most important cytokine receptors that regulate these activities are those that share the common gamma chain (gamma c), i.e. the IL-2R, IL-4R, IL-7R, IL-9R, and IL-15R. As several gamma c-dependent cytokines function non-redundantly at the level of the thymus, it has been difficult to unambiguously delineate what functions these cytokines play during an immune response and in maintaining T cell homeostasis. For example, IL-7R function is required for the production of thymic-derived T cells. Furthermore, our most recent data demonstrate that IL-2 functions non-redundantly at the level of the thymus to regulate self reactivity which is an important component for IL-2-dependent maintenance of peripheral T cell homeostasis. During the last application period, a series of thymic-targeted transgenic mice on various cytokine or cytokine receptor knockout genetic backgrounds were produced in which the T cell developmental defects associated with IL-2 or IL-7 were largely corrected, but the peripheral T cell compartment remained non-responsive to these cytokines. To investigate the redundant activity of IL-4 with IL-2 for T cell growth and effector cell differentiation and with IL-7 for promoting the survival of naive T cells, these transgenic mice have been backcrossed to IL-4-/- mice. Therefore, one major objective of this application is to establish the contribution of the IL-2R/IL-15R, IL-4R, and IL-7R during T cell immune responses in vivo using these mouse models. We will also investigate in vivo the relative role of these cytokine receptors for the survival and homeostasis of naive and memory I cells. Another major objective of the proposed studies is to determine the molecular basis by which IL-2Rbeta signaling programs antigen-activated T cells for extended cytokine dependent growth and differentiation into effector T cells. Our goal here is to relate molecular targets of IL-2R signaling with specific biological responses.
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