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

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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.