The γδ IEL effector API5 masks genetic susceptibility to Paneth cell death

Yu Matsuzawa-Ishimoto, Xiaomin Yao, Akiko Koide, Beatrix M. Ueberheide, Jordan E. Axelrad, Bernardo S. Reis, Roham Parsa, Jessica A. Neil, Joseph C. Devlin, Eugene Rudensky, M. Zahidunnabi Dewan, Michael Cammer, Richard S. Blumberg, Yi Ding, Kelly V. Ruggles, Daniel Mucida, Shohei Koide () and Ken Cadwell ()
Additional contact information
Yu Matsuzawa-Ishimoto: New York University Grossman School of Medicine
Xiaomin Yao: New York University Grossman School of Medicine
Akiko Koide: NYU Langone Health
Beatrix M. Ueberheide: NYU Langone Health
Jordan E. Axelrad: New York University Grossman School of Medicine
Bernardo S. Reis: The Rockefeller University
Roham Parsa: The Rockefeller University
Jessica A. Neil: New York University Grossman School of Medicine
Joseph C. Devlin: New York University Grossman School of Medicine
Eugene Rudensky: New York University Grossman School of Medicine
M. Zahidunnabi Dewan: New York University Grossman School of Medicine
Michael Cammer: New York University Grossman School of Medicine
Richard S. Blumberg: Harvard Medical School
Yi Ding: Geisinger Health
Kelly V. Ruggles: New York University Grossman School of Medicine
Daniel Mucida: New York University Grossman School of Medicine
Shohei Koide: NYU Langone Health
Ken Cadwell: New York University Grossman School of Medicine

Nature, 2022, vol. 610, issue 7932, 547-554

Abstract: Abstract Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn’s disease, a major type of inflammatory bowel disease1–7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn’s disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte–epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05259-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:610:y:2022:i:7932:d:10.1038_s41586-022-05259-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05259-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().