Hvem expression in innate lymphoid cells mediates host defense against intestinal infection

Abstract

Abstract The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor super family (TNFRSF14), has diverse functions in augmenting or inhibiting the immune response. We previously reported that epithelial HVEM signaling at mucosal barriers provides host defense against pathogenic bacteria, but the role of HVEM expression in innate lymphoid cells (ILC) in the mucosal immune system was unknown. To address this issue, we exposed RORgt-Cre × Hvemfl/fl mice with Yersinia enterocolitica (Y. enterocolitica), a small intestine infection model. We found increased bacterial translocation and decreased survival at an early time point. In these mice, Hvem is deleted in NK cells, ILC3 and in all T lymphocytes. Ifng−/− mice also showed reduced survival and increased bacterial translocation early after infection with Y. enterocolitica, demonstrating the importance of this cytokine for host defense. Interestingly, ILC from infected RORgt-Cre × Hvemfl/fl mice produced less IFNg after infection, but IFNg production by CD4+ T cells was not affected. Furthermore, in CD4-Cre × Hvemfl/fl mice, which deleted HVEM only in CD4+ T cells but not in ILCs, were not more susceptible to Y. enterocolitica. Additionally, we found that depletion of ILC from Rag1-deficient mice resulted in increased bacterial translocation and decreased body weight at an early time point. Taken together, our data indicate first, that IFNg production by ILCs, such as NK cells and ILC3, is important for host defense during Y. enterocolitica infection. Second, although the activation of ILCs is regulated by cytokines, our data show that HVEM, a member of the TNF super family, also is required for their ability to respond by producing IFNg early after infection.