Analyses of the role of the TNF family member LIGHT (TNFSF14) in mucosal immune regulation

肠道免疫系统受到严格调节，提供对肠道微生物群及其产物以及对饮食抗原的耐受性，同时保持对入侵病原体发起有效免疫应答的能力。即使在今天，人们对这一精心平衡的体系的监管机制的细节也没有很好的理解。然而，该系统失调的后果在炎性肠病中是明显的，其中粘膜免疫系统的持续激活导致慢性炎症。肿瘤坏死因子（TNF）家族的细胞因子在基本的免疫过程中起着重要的作用。它的成员之一，LIGHT（TNFSF 14），已被证明会导致各种自身免疫综合征，包括肠道炎症时，它是组成性表达的T细胞。相比之下，在结肠炎小鼠模型中，非T细胞上的LIGHT表达是抗炎的，因为LIGHT缺乏大大加速了疾病的发作和严重程度。有趣的是，编码LIGHT的人类基因映射到IBD的易感基因座。本实验将研究LIGHT表达在维持粘膜免疫耐受中的作用，这暗示LIGHT可能是治疗炎症性肠病的新靶点。

The intestinal immune system is tightly regulated providing tolerance against the commensal microbiota and its products as well as against dietary antigens while retaining the ability to launch an effective immune response against invading pathogens. The details of the regulatory mechanisms of this carefully balanced system are not well understood even today. The consequences of dysregulation of this system however, are obvious in inflammatory bowel diseases, where constant activation of the mucosal immune system leads to chronic inflammation. The tumor necrosis factor (TNF) family of cytokines plays important roles in fundamental immunological processes. One of its members, LIGHT (TNFSF14), has been shown to cause a variety of autoimmune syndromes, including intestinal inflammation when it was constitutively expressed on T cells. In contrast, in a mouse model of colitis, LIGHT expression on non-T cells is anti-inflammatory, because LIGHT-deficiency greatly accelerated disease onset and severity. Interestingly, the human gene encoding for LIGHT maps to a susceptibility locus for IBD. The experiments in this proposal will investigate the role of LIGHT expression in the maintenance of mucosal immune tolerance, which implicates LIGHT as a putative new target for the treatment of inflammatory bowel diseases.