Fas in host defense and autoimmune diseases

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Fas (Apo-1, CD95), has been implicated in the regulation of normal and auto-specific immune responses. The role of Fas in autoimmunity is dual: it is involved in the limitation of T cell proliferation in the course of an immune response and it participates in the death of cells targeted by T cells in organ-specific autoimmune responses. Studying mice with conditional deletion of Fas from several cell types we found that mice lacking Fas from antigen presenting cells (ARC) developed systemic autoimmunity. We formulated a hypothesis that a loss of Fas receptor by APC leads to their prolonged survival, extendedpresentation of antigens to T cells, and, thus, contributes to autoimmunity observed in Fas-deficient animals and humans. We are also pursuing a hypothesis that Fas expression by target cells (insulin-producing (I cells) is critical for spontaneous development of an organ-specific autoimmune disease (type 1 diabetes). Using several already developed animal models, we will pursue the following Specific Aims: Specific Aim 1. Determine the contribution of Fas expression by antigen-presenting T cells to normal and auto-specific immune responses. a. We will study the dynamics of Fas-sensitivity of APC and its role in the immune responses. We will also test a hypothesis that Fas-mediated elimination of APC can influence the development of chronic infections. b. We will determine how Fas-mediated death of antigen-presenting cells regulates the development of organ-specific autoimmunity (T1D). Specific Aim 2. Determine the degree of Fas involvement in Bcell destruction during development of autoimmune diabetes. a. We will determine whether fi-cell-specific deletion of Fas affects the development of spontaneous diabetes in NOD model of T1D; b. We will determine the input of other cytotoxic mechanisms into Fas-dependent and Fas-independent apoptosis of & cells. Our studies will open new venues to regulation of immune responses through controlling the lifespan of APC and to prevention of development of autoimmune diseases.