Mucosal TGF-Beta/IL-6 Axis in the Regulation of T Cell Function

描述(申请人提供)：肠上皮细胞和单个核细胞的免疫功能在最近的先天性免疫和获得性免疫研究中受到了密切的研究关注。相比之下，细胞外基质或间质在局部免疫反应中的作用尚未得到严格的评估，也知之甚少。鉴于新近认识到间质在其他器官的免疫串扰和调节中的重要性[1-6]，以及肠道间质在调节粘膜巨噬细胞分化中的作用[7-9]，我们建议研究人类肠道间质在调节T细胞耐受性和促炎功能中的作用。重要的是，调节T细胞的机制似乎在不同的粘膜间隔中有所不同，因为从正常胃粘膜分离的T细胞比来自肠道的T细胞增殖更强烈，并且胃的转化生长因子水平显著低于肠道水平，如我们所示。因此，我们假设：(1)胃和肠粘膜中不协调的CD4+T细胞增殖是由于胃和肠中细菌负荷的不同而导致这些粘膜中不同水平的转化生长因子所致；(2)正常粘膜中的基质相关因子，特别是转化生长因子，促进正常粘膜中的耐受性T细胞，而来自炎症粘膜的其他粘膜衍生因子，特别是IL-6和IL-1，促进促炎和调节性T细胞亚群。我们将通过以下特定目标来检验这些假说：“特定目标1.确定正常胃和肠粘膜中不一致的CD4+T细胞增殖是否是由于间质相关的转化生长因子水平的差异。”具体目的2.确定正常胃粘膜中转化生长因子水平降低是否与正常胃粘膜的无菌特性有关。确定粘膜中的转化生长因子/IL-6轴是否通过转化生长因子1/IL-6促进正常胃和肠粘膜产生耐受性的CD4+T细胞，以及是否通过转化生长因子1/IL-6促进炎性胃肠黏膜中促炎症和调节性的CD4+T细胞的增殖。胃肠道粘膜是与外界环境相互作用的最大粘膜表面，在健康组织中维持对共生细菌和食物抗原的耐受性反应和对入侵固有层的病原体的必要保护性免疫之间的动态平衡。对不同粘膜间隔(胃和小肠)内稳态调节的免疫调节机制以及在T细胞介导的疾病和炎症中这种调节是如何丧失的，人们知之甚少。这一应用将阐明粘膜微环境所起的作用，特别是控制胃和肠粘膜效应性T细胞增殖的耐受性细胞因子和促炎性细胞因子之间的平衡。

DESCRIPTION (provided by applicant): The immunological function of intestinal epithelial and mononuclear cells has received intense investigative attention in recent studies of innate and adaptive immunity. In contrast, the role of the extracellular matrix, or stroma, in local immune responses has not been critically evaluated and is poorly understood. In view of the newly appreciated importance of the stroma in immunological cross-talk and regulation in other organs [1-6] and the role of the intestinal stroma in regulating mucosal macrophage differentiation [7-9], we propose to investigate the function of human intestinal stroma in the regulation of tolerogenic and pro-inflammatory T cell function. Importantly, mechanisms that regulate T cells appear to vary among different mucosal compartments, since T cells isolated from the normal gastric mucosa proliferate more strongly than T cells from the intestine, and gastric TGF levels are significantly lower than intestinal levels, as we show here. Therefore, we hypothesize that (1) Discordant CD4+ T cell proliferation in gastric and intestinal mucosa is due to different levels of TGF in these mucosal compartments in turn due to different bacterial loads in the stomach versus the intestine, and that (2) Stroma-associated factors from normal mucosa, particularly TGF, promote tolerogenic T cells in normal mucosa, whereas other mucosa-derived factors from inflamed mucosa, particularly IL-6 and IL-1, promote pro-inflammatory and regulatory T cell subsets. We will test these hypotheses with the following Specific Aims: " Specific Aim 1. Determine whether the discordant CD4+ T cell proliferation in normal gastric versus intestinal mucosa is due to differences in levels of stroma- associated TGF. " Specific Aim 2. Determine whether the reduced level of TGF in normal gastric mucosa is due to the sterile nature of the normal gastric mucosa. " Specific Aim 3. Determine whether the mucosal TGF/IL-6 axis promotes tolerogenic CD4+ T cells in normal gastric and intestinal mucosa via TGFhi/IL-6lo, and proliferation of pro-inflammatory and regulatory CD4+ T cells in inflamed gastric and intestinal mucosa via TGF hi/IL-6hi. The gastrointestinal mucosa is the largest mucosal surface to interact with the external environment, maintaining in healthy tissue a homeostatic balance between tolerogenic responses to commensal bacteria and food antigens and necessary protective immunity against pathogens that invade the lamina propria. Little is know about the immunoregulatory mechanisms underlying the regulation of homeostasis in different mucosal compartments (stomach and small intestine) and how this control is lost in T cell-mediated disease and inflammation. This application will elucidate the role played by the mucosal microenvironment and in particular, the balance between tolerogenic and pro-inflammatory cytokines that control the proliferation of effector T cells in the gastric and intestinal mucosae.