Regulation of effector T cell function by Blimp-1 in a murine model of colitis

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DESCRIPTION (provided by applicant): Homeostasis in the intestinal mucosa is maintained by a delicate balance between physiological and pathophysiological inflammation that assures efficient response against pathogenic organisms and avoidance of hyperresponsiveness to the commensal flora. Disruption of this balance results in the development of chronic inflammatory conditions, such as ulcerative colitis and Crohn's disease, collectively termed Inflammatory Bowel Disease (IBD). T lymphocytes are major effector cells in IBD, thus, interfering with T cell function could be a potential strategy to treat IBD. However, the precise mechanisms underlying the uncontrolled T cell responses in IBD are not well understood. We and others have recently identified the transcriptional repressor B Lymphocyte Induced Maturation Protein-1 (Blimp-1) as an important regulator of T cell homeostasis and function. Blimp-1 was first known for its crucial role in the terminal differentiation of antibody-secreting plasma cells. Recent studies show that Blimp-1 is also highly expressed in activated T cells. Mice with a T cell-specific deletion of Blimp-1 accumulate "antigen-experienced" cells in the periphery and spontaneously develop colitis, without compromising other organs, indicating that Blimp-1 is required for proper T cell function at the intestinal mucosal. Based on these findings and previous studies in other cell lineages, which established that Blimp- 1 controls several genetic programs, we hypothesize that in T cells Blimp-1 regulates genetic programs crucially important to control responsiveness in the intestinal mucosa, and identification of genetic targets of Blimp-1 in T cells should reveal new molecular pathways implicated in mucosal homeostasis. In the current proposal we will test this hypothesis through the following specific aims: 1) characterize the colitis in the Blimp-1CKO mice to gain insight into the effector mechanisms disrupted in the absence of Blimp-1; and 2) generate and compare Blimp-1 sufficient and deficient colitogenic T cells to identify and validate genes regulated by Blimp-1 in these cells. To accomplish these aims we will use the Blimp-1 CKO mice we have previously generated. First, we will conduct phenotypical and functional analysis to identify the T cell subpopulations causing disease in these mice. Second, we will use adoptive transfer experiments to generate Blimp-1sufficient and deficient colitogenic T cells to be used in gene expression studies (including RNA microarray) to identify molecular pathways controlled by Blimp-1. We anticipate that upon completion of the experiments proposed here, we will have identified new genetic targets of Blimp-1 in T cells and uncovered new pathways important for the regulation of effector T cell function in the intestinal mucosal. Further exploration of these pathways can lead to the development of new therapeutic approaches to treat IBD and potentially other inflammatory disorders. PUBLIC HEALTH RELEVANCE: Unbalanced T cell responses in the intestines result in chronic inflammation of the GI tract. We are seeking to elucidate regulatory mechanisms that control T cell effector function in the intestinal mucosa. Identification of these mechanisms will contribute to development of new therapeutic approaches to treat IBD.