Regulation of effector CD4 T cell subsets during inflammatory bowel disease

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): For over a decade, inflammatory bowel disease (IBD) and other chronic inflammatory disorders including multiple sclerosis and rheumatoid arthritis have been described as Th1-mediated disorders because IFN3- producing CD4 T cells are prevalent in diseased patients and IFN3 strongly activates macrophages, potentiating inflammation. However recent data from animal models of numerous autoimmune/chronic inflammatory disorders suggests that a new lineage of effector CD4 T cells, the IL-17-producing Th17 cells, are responsible for the induction of disease. Interestingly, the onset of these chronic inflammatory diseases is associated with elevated numbers of both IFN3+ and IL-17+ effector CD4 T cells at the sites of inflammation, opening the debate on the individual roles of these effector CD4 T cell populations during disease. In fact, the impact of Th1 CD4 T cells on the development of IBD remains controversial. In certain models of colitis, IFN3 does not appear necessary for disease induction, yet it has been demonstrated that transfer of in vitro- polarized Th1 cells can elicit experimental colitis in mice. Importantly, Th1-associated transcription factors Tbet and STAT4 are required to induce experimental IBD, suggesting a possibly unrecognized role for Th1 effector CD4 T cells in mediating chronic inflammation independent of IFN3 secretion, as these transcription factors are not required for IL-17 production. We hypothesize that Th1 CD4 T cells function to induce IL- 23-dependent colitis in a Tbet-dependent, STAT4-dependent, and non-IFN3-dependent mechanism. We propose the following specific aims to test this hypothesis: Aim 1. To determine the role of in vivo derived IFN3+ CD4 T cells during IL-23-dependent colitis. Aim 2. To determine the prerequisite for Tbet in the CD4 T cell compartment during IBD. Aim 3. To determine the requirement for STAT4 signaling in CD4 T cells during colitis. Collectively these studies are designed to provide new information regarding the cellular mediators of colitis and to precisely define the properties and molecular regulators which control the development of pathogenic CD4 T cells. These findings have the potential to identify new targets for therapeutic and preventative strategies designed to ablate inflammatory bowel disease.