Regulation of immune homeostasis by CD101

微生物、遗传、地理和习惯性因素之间的失调相互作用可能导致先天或获得性免疫系统单个分子的表达或功能不足，并可能导致免疫介导性疾病或增加感染的易感性。然而，调控感染性病原体与患者免疫系统相互作用的分子以及限制炎症过程对侵袭性组织损害的机制还很少被描述。在包括实验性小肠结肠炎在内的三种不同疾病模型中，我们已经发现CD101是一种由胃肠道内的免疫细胞优先表达的负协同刺激分子，是外周免疫稳态的关键调节因子。CD101基因敲除或CD101基因内的等位基因变异导致CD101表达降低，加剧了免疫介导的疾病的严重性，并与调节T细胞功能受损和白细胞介素17反应增强有关。此外，在炎症性肠病患者中，CD101的表达与疾病的活动性和严重程度呈负相关。由于CD101促进髓系细胞释放IL-10，而表达CD101的髓系细胞有助于控制细菌的复制和易位，我们推测CD101发挥抗炎和抗微生物作用，以维持外周免疫耐受。因此，本提案的总体目标是确定CD101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，低氧促进了CD101的表达，而某些类型的细菌抑制了它的表达，并在生理大气氧气条件下在CD101-/-动物和CD101缺陷细胞中积累。因此，我们还提出，由于CD101表达的抑制，病原体破坏了免疫调节过程的诱导。因此，为了剖析CD101、细菌和复杂的氧梯度之间的相互作用，例如在肠道的生理环境中或在炎症过程中，我们的目标是表征a)CD101主要和次要参与的细胞种群以及信号和代谢途径，b)细胞特异性CD101缺失的功能后果，c)调控CD101表达的因素。基于现有的数据，CD101似乎抑制炎症免疫反应和抑制细菌传播。因此，我们认为靶向CD101是治疗自身免疫性、炎症性或感染性疾病的一种潜在策略。

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.