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HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria

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Abstract

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.

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Figure 1: HVEM signalling regulates epithelial immune function by inducing NIK-dependent Stat3 activation.
Figure 2: HVEM is required for host defence against intestinal C. rodentium infection.
Figure 3: CD160 on IELs provides a ligand for HVEM.
Figure 4: HVEM is required for lung epithelial immunity and host defence against S. pneumoniae.

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  • 08 August 2012

    References 34 and 35 were removed from the reference list.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (RO1-AI061516 to M.K.; PO1 DK46763 to M.K.; F32-DK082249 to J.-W.S.; F32-AI083029 to J.L.V.), La Jolla Institute for Allergy and Immunology and the Center for Infectious Disease (LIAI-JAN-2011-CID to J.-W.S.). We thank W. Quyang for providing Reg3γ–Ig fusion protein, and O. Turovskaya for performing histology staining and pathological scoring. We also thank C. Benedict for providing NIKaly/aly mice, K. Pfeffer for providing Hvem−/− and Light−/− mice and K. Murphy for Btla−/− mice. This is manuscript number 1347 from the La Jolla Institute for Allergy and Immunology.

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J.-W.S., A.L., G.K., J.L.V. and S.Z. designed and performed the experiments. H.C. and M.K. contributed to experimental design. J.-W.S. and M.K. wrote the manuscript.

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Correspondence to Mitchell Kronenberg.

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Shui, JW., Larange, A., Kim, G. et al. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488, 222–225 (2012). https://doi.org/10.1038/nature11242

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