Inflammatory Bowel Disease (IBD) is a progressive chronic relapsing and remitting disease that results from an unrestrained inflammatory response to intestinal microbes in a genetically susceptible host. In particular, CD4+ Th17-driven inflammatory response is thought to be instrumental in the augmentation and exacerbation of the pathogenesis of IBD. Previously we identified an important role for the inhibitory receptor, paired Ig-like receptor B (PIRB) in regulation of the initial innate-immune phase of the GI inflammatory response and development of the colitic phenotype. We showed that PIRB restrained innate-immune induced myeloid cell activation and pro- inflammatory cytokine (IL-1?, IL-6 and TNF?) response and that loss of this negative regulatory mechanism led to increased myeloid proinflammatory cytokine production and exacerbation of the colitis phenotype. The contribution of PIRB to the CD4+ T cell-component of the inflammatory response and colitis has previously not been explored. In preliminary experiments we revealed a role for PIRB in the regulation of CD4+ T-cell-dependent colitis. Our data suggest an intrinsic role for PIRB in the regulation of CD4+ T cells and development of the T-cell dependent colitic phenotype and suggests divergent immune regulatory function of inhibitory receptors in innate versus adaptive immune inflammatory responses in the onset of the IBD phenotype. We hypothesize that PIRB regulates CD4+ Th17 development and enhances the pathogenic T-cell immune response in IBD. To test this hypothesis, we propose the following two specifics aims: 1) To define the requirement of PIRB on the CD4+ Th17-dependent colitis; 2) To determine the role of PIRB in CD4+ Th17 differentiation and function. With respect to the expected outcomes, the studies proposed in Aim I are expected to demonstrate a requirement for PIRB in the development and onset of CD4+ Th17-driven colitic phenotype and Aim II are expected to demonstrate that PIRB is required for CD4+ Th17 differentiation and function. Our proposed studies will identify an important role for PIRB regulation of Th17-mediated inflammatory responses and will reveal a divergent role for PIRB in regulating innate and adaptive immune responses. The training plan will take advantage of the opportunities present in the research plan to enhance the training of the applicant in experimental immunology, in vivo mouse disease model systems and provide career development skills which are essential for an independent research scientist. The sponsor and advisors have a strong track record in successful mentorship of graduate students and have expertise in immunology, IBD, and inhibitory receptors that will assure successful completion of the proposed studies and best preparing the applicant to becoming an independent scientific investigator.
Inflammatory Bowel Disease (IBD) is a painful and highly debilitating disease that is of urgent need for new therapeutic approaches for treatment. This project will reveal an important role for inhibitory receptors in the regulation of CD4+ Th17 cells and the unrestrained GI inflammatory response and onset of the clinical manifestations of IBD. Successful completion of the research proposal will lead to the identification of a new target for the treatment of IBD and will aid in further developing a pre-doctoral candidate with interdisciplinary training in immunology.