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.

  • Article
  • Published:

Commensal viruses maintain intestinal intraepithelial lymphocytes via noncanonical RIG-I signaling

Abstract

Much attention has focused on commensal bacteria in health and disease, but the role of commensal viruses is understudied. Although metagenomic analysis shows that the intestine of healthy humans and animals harbors various commensal viruses and the dysbiosis of these viruses can be associated with inflammatory diseases, there is still a lack of causal data and underlying mechanisms to understand the physiological role of commensal viruses in intestinal homeostasis. In the present study, we show that commensal viruses are essential for the homeostasis of intestinal intraepithelial lymphocytes (IELs). Mechanistically, the cytosolic viral RNA-sensing receptor RIG-I in antigen-presenting cells can recognize commensal viruses and maintain IELs via a type I interferon–independent, but MAVS-IRF1-IL-15 axis-dependent, manner. The recovery of IELs by interleukin-15 administration reverses the susceptibility of commensal virus-depleted mice to dextran sulfate sodium–induced colitis. Collectively, our results indicate that commensal viruses maintain the IELs and consequently sustain intestinal homeostasis via noncanonical RIG-I signaling.

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

Access options

Buy this article

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

Fig. 1: Commensal viruses maintain IELs.
Fig. 2: RIG-I recognizes commensal viruses to maintain IELs.
Fig. 3: RIG-I signaling in APCs maintains IELs.
Fig. 4: RIG-I signaling maintains IELs independently of microbiota dysbiosis.
Fig. 5: RIG-I signaling supports IEL proliferation and survival.
Fig. 6: Commensal viruses and RIG-I-MAVS signaling maintain IELs via IL-15.
Fig. 7: Commensal viruses and RIG-I signaling promote IL-15 production via IRF-1.
Fig. 8: Recovery of IELs reverses the colitis susceptibility of commensal virus-depleted mice.

Similar content being viewed by others

Data availability

The EMBL-EBL accession number for viral metagenomics sequences and the 16S ribosomal RNA bacterial sequences is PRJEB27933. The data that support the other findings of this study are available from the corresponding author upon reasonable request.

References

  1. Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reyes, A. et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Virgin, H. W. The virome in mammalian physiology and disease. Cell 157, 142–150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang, T. et al. RNA viral community in human feces: prevalence of plant pathogenic viruses. PLoS Biol. 4, e3 (2006).

    Article  PubMed  CAS  Google Scholar 

  5. Shi, Y. & Mu, L. An expanding stage for commensal microbes in host immune regulation. Cell Mol. Immunol. 14, 339–348 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lopetuso, L. R., Ianiro, G., Scaldaferri, F., Cammarota, G. & Gasbarrini, A. Gut virome and inflammatory bowel disease. Inflamm. Bowel Dis. 22, 1708–1712 (2016).

    Article  PubMed  Google Scholar 

  7. Yang, J. Y. et al. Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-β production. Immunity 44, 889–900 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Broggi, A., Tan, Y., Granucci, F. & Zanoni, I. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat. Immunol. 18, 1084–1093 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cheroutre, H. & Madakamutil, L. Acquired and natural memory T cells join forces at the mucosal front line. Nat. Rev. Immunol. 4, 290–300 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Cheroutre, H. Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu. Rev. Immunol. 22, 217–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Denning, T. L. et al. Mouse TCRαβ+CD8αα intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. J. Immunol. 178, 4230–4239 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Olivares-Villagomez, D. et al. Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease. Proc. Natl Acad. Sci. USA 105, 17931–17936 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jiang, W. et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 210, 2465–2476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu, Q. et al. MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8αα TCRαβ and TCRγδ intestinal intraepithelial lymphocytes. J. Immunol. 176, 6180–6185 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Qiu, Y. et al. TLR2-dependent signaling for IL-15 production is essential for the homeostasis of intestinal intraepithelial lymphocytes. Mediators Inflamm. 2016, 4281865 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Konkel, J. E. et al. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat. Immunol. 12, 312–319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 357, 806–810 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Karst, S. M., Wobus, C. E., Lay, M. & Davidson, J. Virgin HWt. STAT1-dependent innate immunity to a Norwalk-like virus. Science 299, 1575–1578 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Ma, H., Tao, W. & Zhu, S. T lymphocytes in the intestinal mucosa: defense and tolerance. Cell Mol. Immunol. 16, 216–224 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ramanan, D., Tang, M. S., Bowcutt, R., Loke, P. & Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41, 311–324 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Gross, M., Salame, T. M. & Jung, S. Guardians of the gut—murine intestinal macrophages and dendritic cells. Front Immunol. 6, 254 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhu, H. et al. RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer. J. Exp. Clin. Cancer Res. 36, 2 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cheroutre, H. & Lambolez, F. The thymus chapter in the life of gut-specific intraepithelial lymphocytes. Curr. Opin. Immunol. 20, 185–191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gangadharan, D. et al. Identification of pre- and postselection TCRαβ+ intraepithelial lymphocyte precursors in the thymus. Immunity 25, 631–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Fischer, J. C. et al. RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci. Transl. Med. 9, eaag2513 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fujihashi, K., McGhee, J. R., Yamamoto, M., Peschon, J. J. & Kiyono, H. An interleukin-7 internet for intestinal intraepithelial T cell development: knockout of ligand or receptor reveal differences in the immunodeficient state. Eur. J. Immunol. 27, 2133–2138 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Odendall, C. et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat. Immunol. 15, 717–726 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ohteki, T. et al. The transcription factor interferon regulatory factor 1 (IRF-1) is important during the maturation of natural killer 1.1 +T cell receptor-α/β+ (NK1+ T) cells, natural killer cells, and intestinal intraepithelial T cells. J. Exp. Med. 187, 967–972 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ogasawara, K. et al. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391, 700–703 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Das, G. et al. An important regulatory role for CD4+CD8αα T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc. Natl Acad. Sci. USA 100, 5324–5329 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Luda, K. M. et al. IRF8 Transcription-factor-dependent classical dendritic cells are essential for intestinal T cell homeostasis. Immunity 44, 860–874 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Li, X. D. et al. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc. Natl Acad. Sci. USA 108, 17390–17395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bandeira, A. et al. Localization of γ/δ T cells to the intestinal epithelium is independent of normal microbial colonization. J. Exp. Med. 172, 239–244 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Hoytema van Konijnenburg, D. P. et al. Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Cell 171, 783–794 e713 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeng, M. et al. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346, 1486–1492 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Manso, C. F., Bibby, D. F. & Mbisa, J. L. Efficient and unbiased metagenomic recovery of RNA virus genomes from human plasma samples. Sci. Rep. 7, 4173 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chiu, Y. H., Macmillan, J. B. & Chen, Z. J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sweere, J. M. et al. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363, eaat9691 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Michallet, M. C. et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28, 651–661 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Gitlin, L. et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl Acad. Sci. USA 103, 8459–8464 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baldridge, M. T. et al. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection. Science 347, 266–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Thurber, R. V., Haynes, M., Breitbart, M., Wegley, L. & Rohwer, F. Laboratory procedures to generate viral metagenomes. Nat. Protoc. 4, 470–483 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, D. et al. Microarray-based detection and genotyping of viral pathogens. Proc. Natl Acad. Sci. USA 99, 15687–15692 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wood, D. E. & Salzberg, S. L. Kraken: ultrafast metagenomic sequence classification using exact alignments. Genome Biol. 15, R46 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Menzel, P., Ng, K. L. & Krogh, A. Fast and sensitive taxonomic classification for metagenomics with Kaiju. Nat. Commun. 7, 11257 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dieleman, L. A. et al. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin. Exp. Immunol. 114, 385–391 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Akria, J. Tschopp, M. Colonna, Z. Yi and Z. Jiang for providing mice lines. We thank T. Xue for providing AAV plasmids. This work was supported by the National Key R&D program of China (grant no. 2018YFA0507403 to R.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB29030102 to R.Z. and S.Z.), the National Natural Science Foundation of China (grant nos. 31770991 to W.J., 91742202 to R.Z., 81525013 to R.Z., 81722022 to W.J., 81821001 to R.Z., W.J. and S.Z., 81788101 to R.Z.) and the Young Talent Support Program and the Fundamental Research Funds for the Central Universities.

Author information

Authors and Affiliations

Authors

Contributions

L.L., T.G., W.T., B.L., X.Z. and C.L. performed the experiments for this work. L.L., S.Z., W.J. and R.Z. designed the research. L.L., T.G., W.J. and R.Z. wrote the manuscript. W.J. and R.Z. supervised the project.

Corresponding authors

Correspondence to Shu Zhu, Wei Jiang or Rongbin Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, L., Gong, T., Tao, W. et al. Commensal viruses maintain intestinal intraepithelial lymphocytes via noncanonical RIG-I signaling. Nat Immunol 20, 1681–1691 (2019). https://doi.org/10.1038/s41590-019-0513-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-019-0513-z

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