Herpes virus entry mediator (HVEM) is a member of the family of tumor-necrosis factor (TNF) receptors and is reported to be a risk trait for colitis. In Nature, Kronenberg and colleagues show that HVEM expressed on gut and lung epithelial cells contributes to innate mucosal responses. After infection, ligation of HVEM with the costimulator CD160 expressed on intraepithelial lymphocytes and γδ T cells elicits the production of antimicrobial peptides, interleukin 6 (IL-6) and TNF. Blockade of CD160, but not of the other HVEM counter-ligands BTLA or Light, blunts this response in vivo. HVEM signaling stabilizes the kinase NIK, which in this pathway activates the transcription factor STAT3 in an as-yet-unknown way. HVEM and IL-22 act in synergy to protect mucosal tissues, as genetic ablation of either renders mutant mice more sensitive to citrobacter or streptococcal infection. How the HVEM-CD160 interaction is regulated in quiescent tissues and is activated after loss of mucosal integrity should be a focus of future studies.

Nature 488, 222–225 (2012)