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


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.

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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.

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.


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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.

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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.

Correspondence to Shu Zhu or Wei Jiang or Rongbin Zhou.

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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) doi:10.1038/s41590-019-0513-z

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