The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.

The herpes virus entry mediator (HVEM or CD270) is a member of the tumor necrosis factor receptor superfamily (TNFRSF), and therefore it is also known as TNFRSF14. We have recently provided evidence showing a novel signaling pathway downstream of HVEM leading to signal transducer and activator of transcription 3 (STAT3) activation in epithelial cells. As STAT3 regulates the expression of genes important for host defense in epithelial cells, as well as the differentiation of retinoid-related orphan receptor (ROR)γt+ Th17 and innate lymphoid cells (ILC), our finding that HVEM activates STAT3 has revealed fresh insights into the potential regulatory function of HVEM in different cellular contexts. Therefore, although further investigations will be required, HVEM is emerging as a major player in mucosal host defense, capable of regulating several cellular responses.