Cell Reports (Feb 2023)
Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells
- Justin Jacobse,
- Rachel E. Brown,
- Jing Li,
- Jennifer M. Pilat,
- Ly Pham,
- Sarah P. Short,
- Christopher T. Peek,
- Andrea Rolong,
- M. Kay Washington,
- Ruben Martinez-Barricarte,
- Mariana X. Byndloss,
- Catherine Shelton,
- Janet G. Markle,
- Yvonne L. Latour,
- Margaret M. Allaman,
- James E. Cassat,
- Keith T. Wilson,
- Yash A. Choksi,
- Christopher S. Williams,
- Ken S. Lau,
- Charles R. Flynn,
- Jean-Laurent Casanova,
- Edmond H.H.M. Rings,
- Janneke N. Samsom,
- Jeremy A. Goettel
Affiliations
- Justin Jacobse
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA
- Rachel E. Brown
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Jennifer M. Pilat
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Ly Pham
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Sarah P. Short
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Christopher T. Peek
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Andrea Rolong
- Department of Cell and Developmental Biology and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- M. Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Ruben Martinez-Barricarte
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Mariana X. Byndloss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Catherine Shelton
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Janet G. Markle
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Yvonne L. Latour
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Margaret M. Allaman
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA
- James E. Cassat
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA; Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA
- Keith T. Wilson
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Yash A. Choksi
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Christopher S. Williams
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Ken S. Lau
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- Charles R. Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France; The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA
- Edmond H.H.M. Rings
- Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands; Sophia Children’s Hospital, Department of Pediatrics, Erasmus University, Erasmus University Medical Center, Rotterdam, the Netherlands
- Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
- Jeremy A. Goettel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1075J MRB IV, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 2
p. 112128
Abstract
Summary: The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.
