HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.
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.
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
Jr-Wen
JW
Shui
Alexandre
A
Larange
Gisen
G
Kim
Jose Luis
JL
Vela
Sonja
S
Zahner
Hilde
H
Cheroutre
Mitchell
M
Kronenberg
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D058491:Bacterial Load; D002460:Cell Line; D044082:Citrobacter rodentium / Q000276:immunology* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology; D054308:Enteropathogenic Escherichia coli; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D004927:Escherichia coli Infections; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D018928:Immunity, Mucosal / Q000276:immunology*; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology; D015996:Survival Rate; D000097782:NF-kappaB-Inducing Kinase
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D050796:STAT3 Transcription Factor; D000097782:NF-kappaB-Inducing Kinase; C511585:Cd160 protein, mouse; C494087:Stat3 protein, mouse; C506029:Tnfrsf14 protein, mouse