Role of Blimp-1 in preventing chronic intestinal mucosal inflammation.

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DESCRIPTION (provided by applicant): Maintenance of the intestinal mucosa homeostasis is achieved by complex mechanisms, including active downregulation of immune responses1, 2. Disruption of these mechanisms results in chronic immune responses towards the commensal flora which can lead to the development of Inflammatory Bowel Diseases (IBD), 3, 4 and may also contribute to autoimmune diseases at extra-intestinal sites5, 6. CD4+T helper effector (Teff) and regulatory (Treg) lymphocytes are important players in the maintenance of intestinal mucosa homeostasis2, but the molecular mechanisms underlying their function under homeostatic and inflammatory conditions at the intestinal mucosa are not fully understood. B-lymphocyte-induced maturation protein -1 (Blimp-1) is a transcription factor essential for normal development and immunity7. Blimp-1 is expressed in Teff and Treg cells11-15 and T-cell specific deletion of Blimp-1 in mice (Blimp-1CKO) results in development of severe intestinal inflammation11, associated with the accumulation of CD4+ T cells in the colon and aberrant production of inflammatory cytokines11, 16, 17. Polymorphisms in PRDM1 (encoding Blimp-1) are associated with severe inflammatory conditions in humans, including IBD18, 19. Thus, Blimp-1 appears to be a critical regulator of Teff cell terminal differentiation although the speciic transcriptional programs controlled by Blimp-1 in T cells remain largely unknown. The studies proposed here will test the hypothesis that Blimp-1 is required to repress the acquisition of an inflammatory phenotype by mucosal T cells and therefore plays a non redundant role in the maintenance of intestinal mucosa homeostasis. To test this hypothesis we will a) characterize Blimp-1-expressing T cells in the intestinal mucosa and determine the mechanisms regulating Blimp-1 expression; b) identify the mechanisms by which T cell-specific lack of Blimp-1 leads to chronic intestinal inflammation; and c) Determine the molecular mechanisms by which Blimp-1 prevents the acquisition of inflammatory phenotype. We anticipate that the completion of these studies will provide new insights into the genetic programs underlying the differentiation of inflammatory effector T cells, and implicate Blimp-1 as a key repressor of the processes leading to chronic conditions such as IBD.