The long-term objective of this proposal is to investigate the role of HVEM (a TNFR family member) in inflammation and T-cell function. The HVEM-BTLA receptor-ligand pair is known to deliver a co-inhibitory signal to T-cell activation and T-cell mediated immune responses such as colitis.
Our specific aims are first to generate HVEM conditional knockout mice to be used as our working model, and secondly to induce colitis in these mice and evaluate the effect of cell-specific HVEM deletion on colitis pathogenesis. Finally, we examine whether HVEM regulates CD8+ T-cell expansion and memory response, which are important to defense against intracellular pathogens and our understanding of vaccination. In experimental mouse models, the blockade of HVEM signaling ameliorates the severity of spontaneous autoimmune diabetes, while BTLA-deficient mutant mice showed prolonged duration of allergic airway inflammation. In cell culture, HVEM inhibits T-cell proliferation in a BTLA-dependent manner. Together, HVEM-BTLA signaling plays a critical role in dampening T-cell activation and T-cell mediated immune responses both in intro and in vivo. Dr. Kronenberg's laboratory has found that, in a mouse colitis model, HVEM expression by non-T radio-resistant cells in recipient mice significantly prevents colitis progression, while the treatment of inflamed mice with an agonistic anti-BTLA antibody ameliorates colitis acceleration. Therefore, these results form the basis of this proposal that blocking HVEM-BTLA signaling in specific cell population(s) can prevent colitis progression in mice and that the identification of underlying mechanisms may contribute to the design of therapeutic intervene for inflammatory bowel disease (IBD) patients. We will use the most advanced technology (Cre-loxP and FLP-frt systems) to generate conditional knockout mice and test our hypothesis by inducing colitis in these mice with several well-established colitis models. Three different mutant mice have been successfully generated by the applicant in his past research experience and Dr. Kronenberg's laboratory is equipped with well-established systems and experienced personnel for colitis studies. Therefore, we will generate these mutant mice with an expected time frame, and these animals will be available for colitis studies as well as for other immuno-regulation related studies. IBD results from a dysregulated immune response to intestinal antigens. Therapeutic blockade of pro-inflammatory molecules such as TNF alpha has been used clinically to treat IBD patients. Therefore, we believe that HVEM-BTLA signaling may represent a novel anti-inflammatory target that eventually becomes a more potent elixir for IBD treatment.
|Shui, Jr-Wen; Kronenberg, Mitchell (2013) HVEM: An unusual TNF receptor family member important for mucosal innate immune responses to microbes. Gut Microbes 4:146-51|
|Mucida, Daniel; Husain, Mohammad Mushtaq; Muroi, Sawako et al. (2013) Transcriptional reprogramming of mature CD4âº helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 14:281-9|
|Shui, Jr-Wen; Larange, Alexandre; Kim, Gisen et al. (2012) HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488:222-5|
|Shui, Jr-Wen; Steinberg, Marcos W; Kronenberg, Mitchell (2011) Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J Leukoc Biol 89:517-23|
|Steinberg, Marcos W; Shui, Jr-Wen; Ware, Carl F et al. (2009) Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners. Semin Immunopathol 31:207-21|