Although the context is different, our results that HVEM expression by intestinal epithelium provides anti-inflammatory and anti-bacterial protection during infection correlates well with the role of HVEM expressed by an irradiation resistant cell type in recipients, which is required for preventing accelerated T-cell transfer colitis. receptor or as a ligand for the receptor BTLA. Clinically, recently was reported as an inflammatory bowel disease (IBD) risk gene as a result of genome wide association studies (5,6). This suggests HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense and the microbiota. Consistent with this, using mouse models, we have revealed how HVEM is usually involved in colitis pathogenesis, mucosal host defense and epithelial immunity (3,7). Although further studies are needed, our results provide the fundamental basis for understanding why is an IBD risk gene, and they confirm that HVEM is usually a mucosal gatekeeper with multiple regulatory functions in the mucosa. T cells were over reactive exhibiting increased cytokine production. Additionally, mice were reported to be PRT-060318 more susceptible to concanavalin A (ConA)-induced hepatitis and to experimental autoimmune encephalomyelitis (EAE) (8). However, using an animal model of colitis induced by the transfer of CD4+ CD45RBhigh T cells to immune deficient mice, we and others found that host mice receiving T cells had reduced colitis induction and pathogenesis (Table I) (7,9). Therefore, in this model, the function of HVEM in T lymphocytes appears to be pro-inflammatory or co-stimulatory for the T-cell response. Although seemingly contradictory, these inconsistent results could be partially explained by the different functions of HVEM in various immune cell types. In ConA-induced hepatitis and EAE, germline PRT-060318 mice were used such that the phenotype could not be solely ascribed to the function of HVEM in T cells. Instead, the overall phenotype was likely the outcome of different HVEM functions (both co-stimulatory and co-inhibitory) in various cell types involved in these two disease models. In contrast, in the T-cell transfer model of colitis, the genotypes of the donor T lymphocytes and the recipients can be varied to determine the effect of a PRT-060318 genetic variation specifically in T cells. Using this model, we and others found T cells did not expand as efficiently as wild-type T cells after transfer (7,9), implicating intrinsic HVEM signaling in T lymphocytes as a requirement for T-cell expansion, and subsequent colitis pathogenesis. There is also a cell intrinsic role for HVEM signals in CD8+ T lymphocytes following exposure to viral or Mouse monoclonal to TIP60 bacterial infections (Table I) (10,11). Although the initial expansion of CD8+ T cells was not affected by the absence of HVEM, long term survival of the activated cells and the generation of systemic and mucosal memory were impaired. Table I Multiple roles of HVEM in the mucosal immune response Open in a separate window As a reciprocal experiment in the T-cell transfer model of colitis, we made the unexpected observation that this absence of HVEM expression in hosts led to accelerated and exacerbated disease (7). This striking phenotype revealed for the first time that HVEM signaling in cells other than T or B cells is essential for colitis pathogenesis and likely has an important anti-inflammatory role. To gain further insight into the cell type expressing HVEM that prevents severe colitis, we analyzed recipient mice that were reciprocal bone marrow PRT-060318 chimeras. These included mice with bone marrow transferred to irradiated hosts, as well as the opposite. In mice with bone marrow transferred to irradiated hosts, disease following T cell transfer was accelerated and more severe, indicating that HVEM expression in an irradiation resistant cell type is responsible for preventing severe colitis. Together, these experiments established that HVEM signaling in T lymphocytes as well as in other cells have opposing effects on colitis pathogenesis. Consistent with our observation that the effects of HVEM deficiency on intestinal inflammation are cell type-specific, Schaer et al. also showed reduced inflammation when HVEM was not expressed in two colitis models: acute administration of dextran sodium sulfate (DSS) and the T-cell transfer colitis model using T lymphocytes as donor cells (Table I) (9). They further exhibited that HVEM expression was required for the expansion and differentiation of CD4+ T cells during intestinal inflammation. The effect of HVEM deficiency on donor T cells was more pronounced than what was observed in our studies, which is likely due to differences in the genetic background of the mice PRT-060318 as well as environmental differences between mouse.