Control of intestinal inflammation through CD101 expression

通过 CD101 表达控制肠道炎症

• 批准号: 237623172
• 负责人: Professor Dr. Jochen Mattner
• 金额: --
• 依托单位: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237623172?language=en
• 关键词: Control; intestinal; inflammation; through; CD101

Dysregulated host-microbe interactions in genetically susceptible individuals have been implicated in the pathogenesis of inflammatory bowel diseases (IBDs). However, molecules and signalling pathways controlling the interactions of the intestinal microflora with the immune system of the patient and their role in the suppression of intestinal inflammation have been rarely identified. We have recently characterized CD101, a negative costimulatory molecule shared by myeloid and lymphoid cell subsets, as critical factor for the control of T cell proliferation and Th17 differentiation in a chronic T cell transfer colitis model. Recipients of T cells from wild-type mice exhibited less severe intestinal pathology than CD101-/- littermates correlating with an acquisition of CD101-expression on T cells and decreased bacterial translocation. Conversely, human IBD patients exhibited lower numbers of CD101-expressing T cells correlating with increased systemic immune responses to enteric bacterial antigens. Based on these findings we propose that CD101 is a novel clinical marker for tissue-specific inflammation in IBD. Thus, the overall goal of the present proposal is to determine the role of CD101 in directing tissue-specific immune protection. Although the mechanisms by which CD101 interferes with T cell activation are unknown, our preliminary data support the hypotheses that a lack of CD101 expression on T cells inhibits the generation of regulatory T cells, triggers T cell proliferation and Th17 responses and subsequently promotes intestinal inflammation and bacterial translocation. Thus, we aim to: 1) explore the regulation of CD101-expression under physiologic and inflammatory conditions in response to intestinal commensal bacteria; 2) determine the impact of CD101-expression on the protection from colitis; define the role of CD101 on 3) IL-2R- and FoxP3-expression and 4) the generation of regulatory T cell and Th17 responses; 5) specify the interaction(s) of T cells with myeloid cells in the presence and absence of CD101; and 6) correlate the expression of CD101 on T cells in IBD patients to the clinical disease score, the reactivity of serum samples to oligosaccharides of intestinal bacteria and shifts in the balance of Treg-Th17 homeostasis.

遗传易感个体中宿主-微生物相互作用失调与炎症性肠病（IBD）的发病机制有关。然而，控制肠道菌群与患者免疫系统相互作用的分子和信号传导途径及其在抑制肠道炎症中的作用很少被确定。我们最近的特点是CD 101，一个负的共刺激分子共享的骨髓和淋巴细胞亚群，作为关键因素的控制T细胞增殖和Th 17分化的慢性T细胞转移结肠炎模型。来自野生型小鼠的T细胞受体表现出比CD 101-/-同窝小鼠更轻的肠道病理学，这与获得T细胞上的CD 101表达和减少的细菌易位相关。相反，人IBD患者表现出较低数量的表达CD 101的T细胞，这与对肠道细菌抗原的全身免疫应答增加相关。基于这些发现，我们提出CD 101是IBD组织特异性炎症的一种新的临床标志物。因此，本提案的总体目标是确定CD 101在指导组织特异性免疫保护中的作用。虽然CD 101干扰T细胞活化的机制尚不清楚，但我们的初步数据支持以下假设：T细胞上缺乏CD 101表达抑制调节性T细胞的产生，触发T细胞增殖和Th 17应答，随后促进肠道炎症和细菌易位。因此，我们的目标是：2）确定CD 101表达对结肠炎保护的影响;确定CD 101对3）IL-2 R β-和FoxP 3-表达和4）调节性T细胞和Th 17应答的产生的作用; 5）指定在存在和不存在CD 101的情况下T细胞与骨髓细胞的相互作用;和6）将IBD患者中T细胞上的CD 101表达与临床疾病评分相关联，血清样品对肠道细菌寡糖的反应性和Treg-Th 17稳态平衡的变化。