DRAGONFLY KINGDOM NTERNATIONAL SERVICE AGENCY

Highlights

 Endogenous retrovirus sensing is required for commensal-

specific immunity

 Reverse transcription inhibition impairs commensal-induced

immunity in the skin

 cGAS/STING signaling in keratinocytes is required for skin

immunity to the microbiota

 Enhanced endogenous retrovirus expression promotes

microbiota-induced inflammation

Endogenous retroviruses promote homeostatic

and inflammatory responses to the microbiota

Djalma S. Lima-Junior,1,11 Siddharth R. Krishnamurthy,1,2,11 Nicolas Bouladoux,1,2 Nicholas Collins,1 Seong-Ji Han,1

Erin Y. Chen,3 Michael G. Constantinides,1,10 Verena M. Link,1,4 Ai Ing Lim,1 Michel Enamorado,1 Christophe Cataisson,5

Louis Gil,2 Indira Rao,1,6 Taylor K. Farley,1,7 Galina Koroleva,4 Jan Attig,8,9 Stuart H. Yuspa,5 Michael A. Fischbach,3

George Kassiotis,8,9 and Yasmine Belkaid1,2,12,*

1Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National

Institutes of Health, Bethesda, MD 20892, USA

2NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

3Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA

4NIH Center for Human Immunology, Bethesda, MD 20896, USA

5In Vitro Pathogenesis Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National

Institutes of Health, Bethesda, MD 20892, USA

6Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA

7Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of

Oxford, Roosevelt Drive, Oxford OX3 7FY, UK

8Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

9Department of Medicine, Faculty of Medicine, Imperial College London, London W2 1PG, UK

10Present address: Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA

11These authors contributed equally

12Lead contact

*Correspondence: ybelkaid@niaid.nih.gov

https://doi.org/10.1016/j.cell.2021.05.020

SUMMARY

The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in

the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the

skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratino-

cyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon

genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of

ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the mi-

crobiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for

heightened ERV- expression in response to commensal colonization, leading to increased immune re-

sponses and tissue inflammation. Together, our results support the idea that the host may have co-opted

its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-

kingdom dialog that controls both tissue homeostasis and inflammation..........