Regulation of immune homeostasis by CD101

CD101 对免疫稳态的调节

• 批准号: 391702883
• 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: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391702883?language=en
• 关键词: Regulation; immune; homeostasis; CD101

Dysregulated interactions between microbial, genetic, geographic and habitual factors can result in an inadequate expression or function of individual molecules of the innate or adaptive immune system and can cause immune-mediated diseases or increase the susceptibility to infection. However, the molecules, which modulate the interactions of the infectious agents with the immune system of the patient and the mechanisms restricting the inflammatory processes to invasive tissue damage have been rarely characterized. We have identified CD101, a negative costimulatory molecule, preferentially expressed by immune cells within the gastro-intestinal tract, as critical regulator of peripheral immune homeostasis in three different disease models including experimental enterocolitis. The knockout of CD101 or allelic variations within the cd101 gene resulting in a reduced expression of CD101 enhanced the severity of immune-mediated disease and was associated with an impaired regulatory T cell function and augmented interleukin-17 responses. In addition, the expression of CD101 correlated inversely with the activity and severity of disease in patients with inflammatory bowel disease. As CD101 propagated the release of interleukin-10 by myeloid cells and CD101-expressing myeloid cells contributed to the control of bacterial replication and translocation, we hypothesize that CD101 exerts anti-inflammatory and anti-microbial effects in order to maintain peripheral immune tolerance. Thus, the overall goal of the present proposal is to determine the role of CD101 in directing cell-specific immune protection against inflammation and/or infection. Furthermore, our preliminary data suggest that hypoxia promotes CD101-expression, while some classes of bacteria suppress its expression and accumulate in CD101-/- animals and CD101-deficient cells under physiologic atmospheric oxygen conditions. Therefore we also propose that the induction of immunoregulatory processes is disrupted by pathobionts due to the suppression of CD101 expression. Thus, to dissect the mutual interplay of CD101, bacteria and complex oxygen gradients as observed, for example, in the physiologic environment of the gut or during inflammation, we aim to characterize a) the cell populations and signaling and metabolic pathways primarily and secondarily engaged by CD101, b) the functional consequences of a cell-specific CD101 deletion and c) the factors which regulate the expression of CD101.Based on the currently available data CD101 appears to suppress inflammatory immune responses and to inhibit bacterial dissemination. We therefore believe that targeting of CD101 is a potential strategy for the treatment of autoimmune, inflammatory or infectious diseases.

微生物、遗传、地理和习惯因素之间的相互作用失调可导致先天性或适应性免疫系统的单个分子的表达或功能不足，并可引起免疫介导的疾病或增加对感染的易感性。然而，调节感染因子与患者免疫系统相互作用的分子以及将炎症过程限制为侵入性组织损伤的机制很少被表征。我们已经确定了CD 101，一个负的共刺激分子，优先表达的免疫细胞在胃肠道内，作为关键调节外周免疫稳态在三个不同的疾病模型，包括实验性小肠结肠炎。CD 101基因敲除或CD 101基因内等位基因变异导致CD 101表达降低，增强了免疫介导疾病的严重程度，并与调节性T细胞功能受损和白细胞介素-17应答增强相关。此外，CD 101的表达与炎症性肠病患者疾病的活动性和严重程度呈负相关。由于CD 101促进髓系细胞释放白细胞介素-10，并且表达CD 101的髓系细胞有助于控制细菌复制和易位，因此我们假设CD 101发挥抗炎和抗微生物作用以维持外周免疫耐受。因此，本发明的总体目标是确定CD 101在指导针对炎症和/或感染的细胞特异性免疫保护中的作用。此外，我们的初步数据表明，缺氧促进CD 101表达，而某些类别的细菌抑制其表达和积累在CD 101-/-动物和CD 101缺陷细胞在生理大气氧条件下。因此，我们还提出，免疫调节过程的诱导被破坏的致病菌由于抑制CD 101的表达。因此，为了剖析例如在肠道的生理环境中或在炎症期间观察到的CD 101、细菌和复合氧梯度的相互作用，我们的目标是表征a）主要和次要由CD 101参与的细胞群和信号传导和代谢途径，B）细胞特异性CD 101缺失的功能性后果，和c）调节CD 101表达的因子。基于目前可获得的数据，CD 101似乎抑制炎性免疫应答并抑制细菌传播。因此，我们相信靶向CD 101是治疗自身免疫性、炎症性或感染性疾病的潜在策略。