GPR15-guided CD8+ T regulatory cells control intestinal inflammation

Jing Cui; Zuojia Chen; Yan H Cheng; Jia Nie; Maria H Zhu; Chen Xiang; Samuel Chauvin; Wiem Lassoued; Can Liu; Kartika Padhan; Jian Song; Joy A Pai; Borja Ocón; Yifan Yang; Yikun Yao; Ann Y Park; Justin Q Gabrielski; Lixin Zheng; Ping Du Jiang; Yu Zhang; Huie Jing; Leilei Xu; Vicky Chen; Brent A Calabresi; Stefania Pittaluga; David E Kleiner; Clifton L Dalgard; Sinan Sari; Salim Can; Elif Karakoc-Aydiner; Safa Baris; Baran Erman; Michael Field; Jocelyn A Silvester; Gwen Saccocia; Eman K Buhamrah; Khaled Husain; Zahra Chavoshzadeh; Nima Rezaei; Ali İşlek; Hasan Baş; Fatma Dereli Devrez; Rafah Mackeh; Ivan J Fuss; Daniel S Reich; Shania Bailey; Houssein Abdul Sater; James L Gulley; Juraj Kabat; Margery Smelkinson; Sundar Ganesan; Zhenghao Chen; Peter C Grayson; Neelam Redekar; Justin Lack; Zhiyong Lu; Bernice Lo; Hassan Abolhassani; Ahmet Ozen; Athos Bousvaros; Scott B Snapper; Eugene C Butcher; Juan Ravell; Rémy Bosselut; Helen C Su; Chuan Wu; Michael J Lenardo

doi:10.1038/s41586-026-10749-4

GPR15-guided CD8⁺ T regulatory cells control intestinal inflammation

Nature. 2026 Jun 8. doi: 10.1038/s41586-026-10749-4. Online ahead of print.

Authors

Jing Cui^#^{1

2

3}, Zuojia Chen^#⁴, Yan H Cheng^{1

2}, Jia Nie⁵, Maria H Zhu^{1

2}, Chen Xiang^{1

2}, Samuel Chauvin⁶, Wiem Lassoued⁷, Can Liu^{8

9}, Kartika Padhan¹⁰, Jian Song¹⁰, Joy A Pai³, Borja Ocón^{11

12

13}, Yifan Yang¹⁴, Yikun Yao^{1

2}, Ann Y Park^{1

2}, Justin Q Gabrielski^{1

2}, Lixin Zheng^{1

2

3}, Ping Du Jiang^{1

2}, Yu Zhang^{2

15}, Huie Jing^{2

15}, Leilei Xu^{1

2}, Vicky Chen¹⁶, Brent A Calabresi¹⁷, Stefania Pittaluga¹⁸, David E Kleiner¹⁸, Clifton L Dalgard^{19

20}, Sinan Sari²¹, Salim Can^{22

23

24}, Elif Karakoc-Aydiner^{22

23

24}, Safa Baris^{22

23

24}, Baran Erman²⁵, Michael Field²⁶, Jocelyn A Silvester²⁶, Gwen Saccocia²⁶, Eman K Buhamrah²⁷, Khaled Husain²⁸, Zahra Chavoshzadeh²⁹, Nima Rezaei³⁰, Ali İşlek³¹, Hasan Baş³², Fatma Dereli Devrez³², Rafah Mackeh³³, Ivan J Fuss³⁴, Daniel S Reich¹⁷, Shania Bailey⁷, Houssein Abdul Sater⁷, James L Gulley⁷, Juraj Kabat³⁵, Margery Smelkinson³⁵, Sundar Ganesan³⁵, Zhenghao Chen³, Peter C Grayson³⁶, Neelam Redekar¹⁶, Justin Lack¹⁶, Zhiyong Lu¹⁴, Bernice Lo^{33

37}, Hassan Abolhassani^{30

38

39}, Ahmet Ozen^{22

23

24}, Athos Bousvaros²⁶, Scott B Snapper²⁶, Eugene C Butcher^{11

12

13}, Juan Ravell^{40

41}, Rémy Bosselut⁵, Helen C Su^{1

2

15}, Chuan Wu⁴², Michael J Lenardo^{43

44

45}

Affiliations

¹ Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
² Clinical Genomics Program, NIAID, NIH, Bethesda, MD, USA.
³ Calico Life Sciences, South San Francisco, CA, USA.
⁴ Experimental Immunology Branch, National Cancer Institute (NCI), NIH, Bethesda, MD, USA.
⁵ Laboratory of Immune Cell Biology and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
⁶ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Center for Immuno-Oncology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
⁸ Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
⁹ Program in Biological Sciences, University of Maryland, College Park, MD, USA.
¹⁰ Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
¹¹ Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
¹² Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
¹³ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁴ Division of Intramural Research, National Library of Medicine, NIH, Bethesda, MD, USA.
¹⁵ Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
¹⁶ Integrated Data Sciences Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD, USA.
¹⁷ Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
¹⁸ Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
¹⁹ Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA.
²⁰ Center for Military Precision Health, The American Genome Center, Uniformed Services University, Bethesda, MD, USA.
²¹ Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Türkiye.
²² Department of Pediatrics, Division of Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Türkiye.
²³ The Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases, Istanbul, Türkiye.
²⁴ The Isil Berat Barlan Center for Translational Medicine, Istanbul, Türkiye.
²⁵ Institute of Child Health, Can Sucak Research Laboratory for Translational Immunology, Hacettepe University, Ankara, Türkiye.
²⁶ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
²⁷ Pediatric Gastroenterology and Hepatology Department, Al-Amiri Hospital, Kuwait City, Kuwait.
²⁸ Pediatric Gastroenterology, Hepatology and Nutrition Department, Dar Al Shifa Hospital, Kuwait City, Kuwait.
²⁹ Allergy and Clinical Immunology Department, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³⁰ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
³¹ Cukurova University Faculty of Medicine, Department of Pediatrics, Division of Gastroenterology and Hepatology, Adana, Türkiye.
³² Intergen Genetics and Rare Diseases Diagnosis Center, Ankara, Türkiye.
³³ Translational Medicine Department, Research Department, Sidra Medicine, Doha, Qatar.
³⁴ Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
³⁵ Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD, USA.
³⁶ Vasculitis Translational Research Program, National Institute of Arthritis and Musculoskeletal, and Skin Diseases, NIH, Bethesda, MD, USA.
³⁷ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
³⁸ Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
³⁹ Clinic for Pediatric Immunology and Rheumatology, Center for Pediatrics and Adolescent Medicine, University Hospital Bonn, Bonn, Germany.
⁴⁰ Division of Allergy and Immunology, Department of Internal Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.
⁴¹ Department of Internal Medicine, Hackensack Meridian School of Medicine, Nutley, NJ, USA.
⁴² Experimental Immunology Branch, National Cancer Institute (NCI), NIH, Bethesda, MD, USA. chuan.wu@nih.gov.
⁴³ Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. lenardo@calicolabs.com.
⁴⁴ Clinical Genomics Program, NIAID, NIH, Bethesda, MD, USA. lenardo@calicolabs.com.
⁴⁵ Calico Life Sciences, South San Francisco, CA, USA. lenardo@calicolabs.com.

^# Contributed equally.

PMID: 42259915
DOI: 10.1038/s41586-026-10749-4

Abstract

Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer^1,2. The prevalence of the disease is increasing, and there is an urgent need to better understand its pathogenic mechanisms to improve treatment. We show that GPR15-a G-protein-coupled receptor expressed in immune cells and described previously as an entry co-factor for human and simian immunodeficiency viruses³-is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8⁺ T lymphocytes (CD8⁺ T_IGR cells). Deleterious GPR15 gene variants in humans cause defective homing of CD8⁺ T_IGR cells and are associated with severe early-onset IBD. Moreover, CD8⁺ T_IGR cells are reduced in the intestinal mucosa of individuals with sporadic IBD. In mice, GPR15 deficiency impairs colonic homing of CD8⁺ T_IGR cells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8⁺ T_IGR cells potently kill macrophages activated by intestinal damage or disease using Fas ligand and TNF-related weak inducer of apoptosis (TWEAK). The identification of CD8⁺ T_IGR cells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.