The long term objectives of the research project to which these studies relate is to identify natural mechanisms that suppress T cell immunity and promote immune tolerance. The specific focus of studies proposed is to examine molecular and cellular mechanisms that explain how some dendritic cells capable of expressing the enzyme indoleamine 2,3 dioxygenase (IDO-competent DCs) inhibit T cell proliferation, suppress allogeneic T cell responses in vivo, and promote tolerance to skin allografts in mice. Cells expressing IDO protect fetal tissues from attack during pregnancy and suppress T cell immunity to tumors. The significance of studies proposed is that they will provide key new insights into a natural immunoregulatory mechanism that may be manipulated to provide new therapeutic approaches to enhance anti-tumor and anti-pathogen immunity, and to promote tolerance in patients with autoimmune diseases, or who have received organ or tissue allografts, in published and preliminary studies we show that IDO-transgenic mice exhibited enhanced tolerance to skin allografts, while IDO deficient mice exhibited defects in acquired tolerance and CTLA4-Ig-mediated suppression of allogeneic T cell responses. Studies conducted in vitro revealed that minor subsets of murine splenic DCs expressed IDO and blocked T cell proliferation in response to CTLA4-Ig treatment, or when cultured with regulatory T cells (Tregs) expressing surface CTLA4. Hence, the hypothesis that guides this proposal is that CTLA4+ Tregs and IDO-competent DCs collaborate to form a regulatory network that suppresses effector T cell responses and promotes tolerance. Studies proposed in Aim 1 examine the mechanisms that induce IDO gene expression following B7 ligation. Studies in Aim 2 examine how minor subsets of IDO-competent DCs promote dominant T cell suppression and studies in Aim 3 examine the relationship between IDO expression and Treg development and function.
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