HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria

Abstract

The TNF receptor HVEM is shown to control the innate immune response to pathogenic bacteria by regulating mucosal epithelial cells in the intestine and lung. The tumour-necrosis-factor receptor HVEM is shown to control the innate immune response to pathogenic bacteria by mucosal epithelial cells in the intestine and lungs. Engagement of HVEM activates Stat3 and leads to production of antimicrobial peptides, chemokines and inflammatory cytokines. Mice deficient in HVEM (herpes virus entry mediator, also called TNFSFR 14) are highly susceptible to intestinal infection with Citrobacter rodentium, a model for the enteropathogenic Escherichia coli infection, and to airway infection by Streptococcus pneumoniae. The authors suggest that HVEM may be a master orchestrator of intestinal and lung epithelial immune responses to bacteria, and that therapeutic targeting of HVEM with agonists could stimulate host defences. The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response1. HVEM was recently reported as a colitis risk locus in patients2, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM3, 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 infection4,5,6, 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 infection9, 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.