Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Change history

  • 08 August 2012

    References 34 and 35 were removed from the reference list.

References

  1. Murphy, T. L. et al. Slow down and survive: enigmatic immunoregulation by BTLA and HVEM. Annu. Rev. Immunol. 28, 389–411 (2010)

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genet. 43, 246–252 (2011)

    Article  CAS  PubMed  Google Scholar 

  3. Steinberg, M. W. et al. A crucial role for HVEM and BTLA in preventing intestinal inflammation. J. Exp. Med. 205, 1463–1476 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mundy, R. et al. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697–1706 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. Ma, C. et al. Citrobacter rodentium infection causes both mitochondrial dysfunction and intestinal epithelial barrier disruption in vivo: role of mitochondrial associated protein (Map). Cell. Microbiol. 8, 1669–1686 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. LeBlanc, P. M. et al. Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe 3, 146–157 (2008)

    Article  CAS  PubMed  Google Scholar 

  7. Maeda, M. et al. Murine CD160, Ig-like receptor on NK cells and NKT cells, recognizes classical and nonclassical MHC class I and regulates NK cell activation. J. Immunol. 175, 4426–4432 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. Anumanthan, A. et al. Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes. J. Immunol. 161, 2780–2790 (1998)

    CAS  PubMed  Google Scholar 

  9. Nakamatsu, M. et al. Role of interferon-gamma in Vα14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs. Microbes Infect. 9, 364–374 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. Schaer, C. et al. HVEM signalling promotes colitis. PLoS ONE 6, e18495 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Artis, D. et al. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nature Rev. Immunol. 8, 411–420 (2008)

    Article  CAS  Google Scholar 

  12. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008)

    Article  CAS  PubMed  Google Scholar 

  13. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marsters, S. A. et al. Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-κB and AP-1. J. Biol. Chem. 272, 14029–14032 (1997)

    Article  CAS  PubMed  Google Scholar 

  15. Jin, W. et al. Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK. Blood 113, 6603–6610 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wolk, K. et al. Biology of interleukin-22. Semin. Immunopathol. 32, 17–31 (2010)

    Article  CAS  PubMed  Google Scholar 

  19. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004)

    Article  CAS  PubMed  Google Scholar 

  21. Brand, S. et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G827–G838 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Torchinsky, M. B. et al. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation. Nature 458, 78–82 (2009)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Tachiiri, A. et al. Genomic structure and inducible expression of the IL-22 receptor alpha chain in mice. Genes Immun. 4, 153–159 (2003)

    Article  CAS  PubMed  Google Scholar 

  24. Gelebart, P. et al. Interleukin 22 signaling promotes cell growth in mantle cell lymphoma. Transl. Oncol. 4, 9–19 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cheung, T. C. et al. Unconventional ligand activation of herpesvirus entry mediator signals cell survival. Proc. Natl Acad. Sci. USA 106, 6244–6249 (2009)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Quinton, L. J. et al. Functions and regulation of NF-κB RelA during pneumococcal pneumonia. J. Immunol. 178, 1896–1903 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Mizgerd, J. P. et al. Animal models of human pneumonia. Am. J. Physiol. Lung Cell. Mol. Physiol. 294, L387–L398 (2008)

    Article  CAS  PubMed  Google Scholar 

  28. Quinton, L. J. et al. NF-κB and STAT3 signaling hubs for lung innate immunity. Cell Tissue Res. 343, 153–165 (2011)

    Article  CAS  PubMed  Google Scholar 

  29. Quinton, L. J. et al. Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am. J. Respir. Cell Mol. Biol. 38, 699–706 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rooney, I. A. et al. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J. Biol. Chem. 275, 14307–14315 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lebeis, S. L. et al. Interleukin-1 receptor signaling protects mice from lethal intestinal damage caused by the attaching and effacing pathogen Citrobacter rodentium . Infect. Immun. 77, 604–614 (2009)

    Article  CAS  PubMed  Google Scholar 

  33. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009)

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Mitchell Kronenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-18. (PDF 8046 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11242

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing