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

描述（由申请人提供）：肠上皮细胞和单核细胞的免疫功能在最近的先天免疫和适应性免疫研究中受到了广泛的关注。相比之下，细胞外基质或基质在局部免疫反应中的作用尚未得到严格评估，而且对其了解甚少。鉴于基质在其他器官的免疫互导和调节中的重要性[1-6]以及肠基质在调节粘膜巨噬细胞分化中的作用[7-9]，我们提出研究人肠基质在调节耐受性和促炎T细胞功能中的作用。重要的是，调节T细胞的机制似乎在不同的粘膜区室中有所不同，因为从正常胃粘膜分离的T细胞比从肠道分离的T细胞增殖更强，并且胃TGF水平明显低于肠道水平，正如我们在这里所示。因此，我们假设：(1)胃和肠粘膜中CD4+ T细胞增殖不一致是由于胃和肠中细菌负荷不同导致这些粘膜腔室中TGF水平不同所致；(2)正常粘膜中的基质相关因子，特别是TGF促进正常粘膜中的耐受性T细胞，而炎症粘膜中的其他粘膜源性因子，特别是IL-6和IL-1，促进促炎和调节性T细胞亚群。我们将用以下具体目标来检验这些假设：确定正常胃粘膜与肠粘膜CD4+ T细胞增殖不一致是否由于基质相关TGF水平的差异。具体目标2。判断正常胃黏膜TGF水平降低是否由于正常胃黏膜无菌性所致。具体目标3。确定粘膜TGF/IL-6轴是否通过TGF - hi/IL-6lo促进正常胃肠黏膜耐受性CD4+ T细胞，是否通过TGF - hi/IL-6hi促进炎症性胃肠黏膜促炎调节性CD4+ T细胞增殖。胃肠道粘膜是与外界环境相互作用的最大的粘膜表面，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侵入固有层的病原体的必要保护性免疫之间的稳态平衡。关于不同粘膜区室（胃和小肠）内稳态调节的免疫调节机制，以及这种控制如何在T细胞介导的疾病和炎症中丢失，我们知之甚少。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中效应T细胞增殖的耐受性和促炎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.