Regulation of Mucosal Immune Responses by Intestinal Antigen Presenting Cells

理解IBD肠道免疫反应的一个重要挑战仍然是一个明确的挑战。 理解在增强肠道耐受性与允许对病原微生物的适当粘膜免疫应答之间的关键免疫平衡。粘膜驻留抗原呈递细胞，特别是树突状细胞和巨噬细胞，在这方面有很大的希望，因为它们可以摄取肠道细菌并诱导不同类型的免疫应答，例如促炎性（Th 1/Th 17）与调节性（Treg/Tr 1/Th 3）T细胞应答。然而，固有层抗原呈递细胞群体及其功能仍然没有充分的定义。因此，本提案的总体目标是对肠道中的抗原呈递细胞如何发挥作用以调节粘膜耐受性和免疫性获得更强的基本理解。 该建议的主要焦点是彻底研究固有层巨噬细胞的特征不明显的群体，并将其与粘膜DC进行比较。推动这项研究的中心假设是，肠固有层巨噬细胞独特的抗炎特征可能促进调节性T细胞和粘膜耐受的诱导。将通过分析固有层巨噬细胞的能力以及在体外和体内调节T细胞应答的能力（具体目标1），通过比较粘膜巨噬细胞和DC的重叠和不同的质量和功能（具体目标2），以及通过分析这些巨噬细胞和DC在肠中T细胞分化和炎症调节中的作用（具体目标3）来检验该假设。

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).