Transforming Growth Factor beta in T-Cell Homeostasis and Tolerance

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DESCRIPTION (provided by applicant): Project Summary: T-cell homeostasis is an essential process for maintaining peripheral lymphocyte pool size. T cells must provide a diverse repertoire of antigen recognition to effectively recognize and destroy pathogens that they encounter. Antigen-specific T-cell pools are expanded during viral infection and are contracted after the initial viral clearance to make space for the entire T-cell repertoire. This is a tightly regulated process since the space available for lymphocytes is limited. Transforming Growth Factor ? signaling is required to prevent autoimmune disease and dysregulation of T-cell homeostasis. Normally, T cells must interact with self-MHC molecules for their survival, maintenance and homeostatic expansion, but under some pathological conditions such interactions cause inappropriate activation of T cells leading to autoimmune disease. Characterization of TGF??-deficient mice has revealed that their autoimmune disease results from spontaneous activation of their T cells in response to self-antigen recognition by having an inappropriately low threshold level of activation through a Calcium-Calcineurin signaling cascade. Elimination of T cells or their self-antigen recognition is sufficient to prevent autoimmune disease in these mice, and reducing calcineurin signaling drastically attenuates their autoimmune disease. In addition, it is known that without TGF? signaling there are less T-regulatory cells, the cells that mediate immune tolerance. Here we propose to investigate mechanisms and processes underlying the role of TGF? in the regulation of T-cell homeostasis and self-tolerance. Firstly, we will address how TGF?1 regulates T-cell pool size using an Ovalbumin-specific T-cell receptor transgenic TGF?1-deficient mouse strain. Adoptive transfer and Ovalbumin activation studies will be used. Secondly, we will study the role of TGF?? and its signaling pathways in peripheral T-cell regulation. T-regulatory cell transfer to effect tolerizing activity will be performed and the passive or infectious nature of that activity will be determined. Relevance: Dysregulation of homeostatic process has been implicated in many human diseases such as AIDS, leukemia, inflammatory bowl disease, and autoimmune diseases such as type 1 diabetes, multiple sclerosis and arthritis. Processes involved in T-cell homeostasis such as lymphocyte activation, survival and death are presently under intensive study because of their relevance to these diseases. The information gained from these studies will be useful for developing therapies for the induction of tolerance during transplantation, for enhancing tumor vaccine potential, and for the prevention of autoimmune disease.