Regulation of Mucosal Immune Responses by Intestinal Antigen Presenting Cells

了解IBD肠道免疫反应的一个重要挑战仍然是明确的 了解在加强肠道耐受性，同时允许对病原微生物作出适当的粘膜免疫反应之间的关键免疫平衡。粘膜驻留的抗原提呈细胞，特别是树突状细胞和巨噬细胞，在这方面很有希望，因为它们可以摄取肠道细菌并诱导不同类型的免疫反应，例如促炎(Th1/Th17)和调节性(Treg/TR1/Th3)T细胞反应。然而，固有层抗原提呈细胞群体及其功能仍未得到充分界定。因此，这项建议的总体目标是对肠道中的抗原提呈细胞如何调节粘膜耐受性和免疫功能有更深入的基础了解。 这项建议的主要焦点是彻底调查特征不佳的固有层巨噬细胞群，并将它们与粘膜树突状细胞进行比较。推动这项研究的中心假设是，肠道固有层巨噬细胞独特的抗炎特征可能促进调节性T细胞的诱导和粘膜耐受。这一假设将通过分析固有层巨噬细胞和调节体外和体内T细胞反应的能力(特定目标1)、通过比较粘膜巨噬细胞和DC重叠和不同的性质和功能(特定目标2)以及通过分析这些巨噬细胞和DC在T细胞分化和肠道炎症调节中的作用(特定目标3)来验证。

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).