CD4+ regulatory T cells (TR) expressing the transcription factor Foxp3 are potent anti-inflammatory cells that dampen immune responses to both self- and foreign-antigens. Although TR are essential for prevention of autoimmunity, their homeostasis and function must be tightly regulated to ensure that the initiation, progression and termination of the immune response proceed appropriately when needed. Cytokines are a group of proteins that help control T cell development, homeostasis, activation, function, migration and death, having a profound impact on both the magnitude and quality of the immune response. Although the influences of many cytokines on conventional CD4+ and CD8+ effector T cells have been extensively studied, the ways in which most cytokines impact the homeostasis and function of TR are still poorly understood. TR were initially identified by their constitutive expression of the high affinity IL-2 receptor component CD25, and IL-2 is required for proper TR function in vivo. However, the ways in which other pro- and anti-inflammatory cytokines impinge upon IL-2-depndent signaling to modulate TR activity during infection and autoimmunity are poorly understood. Type-1 interferons are a group of closely related cytokines that are highly expressed during most viral infections. The type-1 interferons generally limit cell proliferation, and potently activate innate anti-viral activities within nearly all cells. In addition, type-1 interferon strongly potentiates the clonal expansion of virus- specific CD8+ and CD4+ T cells. Because of these activities, intact type-1interferon signaling is essential for proper anti-viral immunity in both mice and humans. However, aberrant expression of type-1 interferon is associated with several systemic autoimmune diseases. Surprisingly, despite their important functions in anti- viral immunity and development of autoimmunity, the direct effects of type-1 interferon on the homeostasis and function of TR have not been extensively studied. Our preliminary data demonstrate that TR homeostasis is dramatically altered during the course of acute viral infection, and that this is due in part to the production of type-1 interferons. In thi proposal, we will follow up on these important new findings, and utilize a number of cellular and molecular approaches to examine how type-1 interferon combines with IL-2 to control TR activity in vivo. We will then explore how this in turn influences the outcome of acute and chronicviral infection, and development of type-1 interferon-dependent autoimmunity. Finally, we will explore the molecular mechanisms by which the type-1 interferons influence TR activity.
Cytokines are a group of proteins that help control T cell development, homeostasis, activation, function, migration and death, having a profound impact on both the magnitude and quality of the immune response. The proposed studies will determine how the cytokines IL-2, IL-15 and type-1 interferon control regulatory T cell homeostasis and function in different immunological contexts. Cytokines have been successfully targeted to develop new drugs against a range of immune-mediated diseases, and understanding how they act on regulatory T cells will provide new opportunities to therapeutically manipulate their activity in the context of autoimmunity, cancer and infection.
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