An Important challenge in understanding intestinal immune responses in IBD remains a clear understanding of the critical immunological balance between enforcing intestinal tolerance, while allowing for appropriate mucosal Immune responses to pathogenic microbes. Mucosa-resident antigen presenting cells, particularly dendritic cells and macrophages, hold great promise in this regard because they can uptake enteric bacteria and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. However, lamina propria antigen presenting cell populations and their functions remain inadequately defined. Therefore, the overall goal of this proposal Is gain a stronger fundamental understanding of how antigen presenting cells in the intestine function to modulate mucosal tolerance and Inimunlty. The main focus of this proposal Is to thoroughly investigate the poorly characterized population of lamina propria macrophages and to compare them to mucosal DCs. The central hypothesis driving this research is that the unique anti-Inflammatory signature of intestinal lamina propria macrophages may promote the induction of regulatory T cells and mucosal tolerance. This hypothesis will be tested by analyzing the ability of lamina propria macrophages and to modulate T cell responses in vitro and in vivo (Specific Aim 1), by comparing of overlapping and distinct qualities and functions of mucosal macrophages and DCs (Specific Aim 2), and by analyzing the roles of these macrophages and DCs in T cell differentiation and regulation of inflammation in the intestine (Specific Aim 3).
Information gained from these studies will represent major advancements In the understanding of intestinal antigen presenting cell functions as they relate to the induction of tolerogenic and immunogenic immune responses. This knowledge could ultimately aid in the rational design of immunotherapeutics to treat IBD.
|Geem, Duke; Ngo, Vu; Harusato, Akihito et al. (2016) Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell Compartment. Cell Mol Gastroenterol Hepatol 2:274-280|
|Dunham, Richard M; Thapa, Manoj; Velazquez, Victoria M et al. (2013) Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J Immunol 190:2009-16|
|Khounlotham, Manirath; Kim, Wooki; Peatman, Eric et al. (2012) Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. Immunity 37:563-73|