Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice
Abstract
Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp³⁺ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
Copyright and License
© 2023 Vasquez Ayala et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Acknowledgement
We thank members of the Chu lab for technical support and helpful discussions, and A. Khosravi and G. Sharon for critical reading of the manuscript. We thank Drs. Victor Nizet (University of California, San Diego, La Jolla, CA, USA) and Manuela Raffatellu (University of California, San Diego, La Jolla, CA, USA) for sharing bacterial strains and to the Flow Cytometry Core Facility at the La Jolla Institute and Cheryl Kim for their expertise and instrument support.
This work was supported by R00 DK110534 and P30 DK120515 from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), R01 A167860 from the National Institute of Allergy and Infectious Diseases (NIAID), and the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines to H. Chu; and NIAID AI108651 and AI163813 to L-F. Lu and AI125247 to B. Min. Additional support was provided to H. Chu by the Canadian Institute for Advanced Research Humans and the Microbiome Program, The Hartwell Foundation, and Japan Agency for Medical Research and Development (JP233fa627003). M. Carrillo Terrazas was supported by T32 DK007202 (NIDDK), the National Academies of Sciences, Engineering and Medicine through the Predoctoral Fellowship of the Ford Foundation, and the Howard Hughes Medical Institute Graduate Fellowships grant (GT15123).
Contributions
H. Chu conceived the project and designed the experiments. A. Vasquez Ayala, C-Y. Hsu, K. Matsuo, E. Buzun, M. Carrillo Terrazas, L.R. Loomis, H-H. Lu, R.R. Gerner, and H. Chu performed the experiments. J.H. Park and P. Rivaud performed the single-cell analysis experiments, R.E. Oles performed computational analyses, and A. Vasquez Ayala, K. Matsuo, C-Y. Hsu, H-H. Lu, and H. Chu analyzed the data. M. Thomson supported and supervised the single-cell RNA sequencing studies. Z. Zhang, S. Kim, L-F. Lu, and B. Min provided key resources and technical guidance. H. Chu supervised the project and wrote the manuscript with contributions from all authors.
Data Availability
The data are available from the corresponding author upon reasonable request. The single-cell RNA sequencing data underlying Fig. 4 are openly available in the NCBI Gene Expression Omnibus (GEO) under accession number GSE248021.
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Additional details
- ISSN
- 1540-9538
- PMCID
- PMC10716256
- National Institutes of Health
- R00 DK110534
- National Institutes of Health
- P30 DK120515
- National Institutes of Health
- R01 A167860
- Chiba University
- University of California, San Diego
- National Institutes of Health
- AI108651
- National Institutes of Health
- AI163813
- National Institutes of Health
- AI125247
- Canadian Institute for Advanced Research
- Hartwell Foundation
- Japan Agency for Medical Research and Development
- JP233fa627003
- National Institutes of Health
- NIH Predoctoral Fellowship T32 DK007202
- National Academies of Sciences, Engineering, and Medicine
- Ford Foundation
- Howard Hughes Medical Institute
- GT15123
- Caltech groups
- Division of Biology and Biological Engineering, Tianqiao and Chrissy Chen Institute for Neuroscience