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

粘膜 TGF-β/IL-6 轴在 T 细胞功能调节中的作用

• 批准号: 7860420
• 负责人: LESLEY E SMYTHIES
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860420
• 关键词: Antigens; Attention; CD4 Positive T Lymphocytes; Cell physiology; Cells; Conditioned Culture Media; Disease; Down-Regulation; Environment; Epithelial; Epithelial Cells; Equilibrium; Extracellular Matrix; Food; Gastric mucosa; Helicobacter pylori; Homeostasis; Human; Immune response; Immunity; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Intestinal Mucosa; Intestines; Invaded; Lamina Propria; Mediating; Messenger RNA; Mononuclear; Mucous Membrane; Nature; Organ; Play; Proliferating; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Small Intestines; Source; Sterility; Stomach; Surface; System; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transforming Growth Factor beta; Up-Regulation; Urease; Virulence Factors; adaptive immunity; commensal microbes; cytokine; gastrointestinal; macrophage; mutant; neutralizing antibody; pathogen; response

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.

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性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应答中的作用尚未得到严格评估，也知之甚少。鉴于最近认识到基质在其他器官中的免疫串扰和调节中的重要性[1-6]以及肠基质在调节粘膜巨噬细胞分化中的作用[7-9]，我们建议研究人肠基质在调节致耐受性和促炎性T细胞功能中的功能。重要的是，调节T细胞的机制似乎在不同的粘膜隔室中有所不同，因为从正常胃粘膜分离的T细胞比来自肠的T细胞增殖更强烈，并且胃TGF水平显著低于肠水平，如我们在这里所示。因此，我们假设（1）胃和肠粘膜中不一致的CD 4 + T细胞增殖是由于这些粘膜区室中不同水平的TGF，而这些粘膜区室又是由于胃与肠中不同的细菌负荷，以及（2）来自正常粘膜的基质相关因子，特别是TGF，促进正常粘膜中的致耐受性T细胞，而来自发炎粘膜的其他粘膜衍生因子，特别是IL-6和IL-1，促进促炎性和调节性T细胞亚群。我们将用以下具体目标来检验这些假设：“具体目标1。确定正常胃粘膜与肠粘膜中不一致的CD 4 + T细胞增殖是否是由于基质相关TGF水平的差异。具体目标2。确定正常胃粘膜中TGF水平的降低是否是由于正常胃粘膜的无菌性。具体目标3。确定粘膜TGF/IL-6轴是否通过TGF hi/IL-6 lo促进正常胃和肠粘膜中的致耐受性CD 4 + T细胞，以及通过TGF hi/IL-6 hi促进发炎胃和肠粘膜中的促炎性和调节性CD 4 + T细胞的增殖。胃肠道粘膜是与外部环境相互作用的最大粘膜表面，在健康组织中维持对肠道细菌和食物抗原的致耐受性应答与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。很少有人知道的免疫调节机制的调节稳态在不同的粘膜隔室（胃和小肠），以及如何失去这种控制在T细胞介导的疾病和炎症。本申请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细胞增殖的致耐受性和促炎性细胞因子之间的平衡。