Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis

Affiliations

¹ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA.
² Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Chemistry, University of Chicago, Chicago, IL, USA.
⁴ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA.
⁵ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.
⁶ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
⁸ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
¹⁰ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA; Paris City University, Imagine Institute, Paris, France. Electronic address: bjabri@bsd.uchicago.edu.

PMID: 40154490
PMCID: PMC12235565 (available on 2026-04-09)
DOI: 10.1016/j.chom.2025.03.004

Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis

Wioletta Lisicka et al. Cell Host Microbe. 2025.

. 2025 Apr 9;33(4):498-511.e10.

doi: 10.1016/j.chom.2025.03.004. Epub 2025 Mar 27.

Affiliations

¹ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA.
² Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Chemistry, University of Chicago, Chicago, IL, USA.
⁴ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA.
⁵ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.
⁶ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
⁸ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
¹⁰ Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA; Paris City University, Imagine Institute, Paris, France. Electronic address: bjabri@bsd.uchicago.edu.

PMID: 40154490
PMCID: PMC12235565 (available on 2026-04-09)
DOI: 10.1016/j.chom.2025.03.004

Abstract

Immunoglobulin A (IgA) is the predominant immunoglobulin isotype in mammals, primarily secreted at type I mucosal surfaces. Despite its abundance, the precise role of secretory IgA in the intestinal lumen, where it coats a diverse array of commensal microbiota, has remained elusive. Our study reveals that germinal center IgA responses are essential for preventing chronic colonization of the gut by specific viruses. In the absence of IgA, chronic viral colonization triggers an antigen-driven expansion of CD8αβ⁺ intraepithelial lymphocytes (IELs). Although these IELs are unable to clear the virus, they contribute to maintaining homeostasis by regulating its load and type I interferon responses. Consequently, IgA deficiency increases susceptibility to colitis in genetically susceptible hosts or following chemical induction but only in the presence of viral pathobionts requiring IgA for their clearance. These findings underscore the potential vulnerability of IgA-deficient individuals to immunopathology when exposed to selective viral pathobionts.

Keywords: Astrovirus; colitis; immunoglobulin A; intraepithelial lymphocytes; Νorovirus.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis

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Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis

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