Crohn's disease and ulcerative colitis are T cell-mediated disorders induced by aggressive mucosal 004""""""""^ cell responses to commensal enteric bacteria. Interleukin-10 (IL-10) is a key inhibitor of effector T cells and mediator of mucosal homeostasis. Bacteria stimulate ILIO production by regulatory T cells, B cell subsets, macrophages, dendritic cells, neutrophils and keratinocytes. Multiple studies implicate IL-10-producing regulatory CD4*T cell subsets (Treg, TRI) in mucosal homeostasis. However, we and others reported that IL-10 producing antigen presenting cells (APC) prevent onset of bacterial antigen-driven CD4''cell TH1/TH17- mediated chronic experimental colitis, maintain in vivo Treg activity during colitis and activate FoxP3* 004* T cells in vitro. Understanding how bacterial products stimulate IL-10 production is based on in vitro studies using cells not native to the intestine and narrowly defined stimulants with conflicting results in different cell types. Therefore mechanistic studies in physiologically-stimulated mucosal immune cells are needed. Our preliminary data using a novel germ-free ILIO reporter mouse (IL-10^'^'''') show that colonization with commensal bacteria stimulates IL-10 production by intestinal lamina propria innate and adaptive immune cells within 5 days, colonic lL-10-producing B cells are highly expanded in experimental colitis, co-transfer of IL-10 producing but not IL-10""""""""'"""""""" B cells attenuate colitis in a CD4 transfer model, ex vivo stimulation with TLR ligands activates IL-10 production by LP innate immune cells from GF and to a lesser extent, SPF mice, and that intestinal IL-10 expression is increased in experimental colitis and IBD tissues. Hvpothesis: Commensal enteric bacteria, their TLR and NOD-like receptor (NLR) ligands and inflammatory molecules stimulate immunosuppressive IL-10 production by LP M0, DC and B ceH subsets that is a primary determinant of protective (regulatory) vs. pathogenic (effector) mucosal immune responses.
Aim 1 : Determine the mechanisms by which commensal bacterial species and their TLR and NLR ligands Induce protective IL-10 in mucosal Innate Immune cells. These studies focus on induction of constitutive IL-10 production in LP cells from GF mice and zebrafish exposed to commensal bacteria, with key pathways studies in human lamina propria cells. A. Determine the relative roles of various TLR and NLR signaling in inducing IL-10 production by mucosal innate immune cells B. Determine whether different commensal bacterial species selectively induce IL-10 in LP innate cells taking advantage of our gnotobiotic animal facility (Core A).
Aim 2 : Identify the types of intestinal innate immune cells responsible for mucosal IL-10 secretion and protection against colitis. A. Cell lineage production of IL-10. We will determine the kinetics of IL-10 production by LPMNC subsets in GF IL-IO^^""""""""""""""""^ mice after bacterial colonization and secretion of IL-10 by LP cell subsets stimulated with CBL B. Functional studies will compare functional regulation of CBL-activated effector CD4* cells by co-cultured WT and IL-10-/- APC subsets.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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University of North Carolina Chapel Hill
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