Abstract
Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161 + regulatory T (T reg ) cells as a distinct, highly suppressive population of T reg cells that mediate wound healing. These T reg cells were enriched in intestinal lamina propria, particularly in Crohn’s disease. CD161 + T reg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on T reg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161 + T reg cell signature in Crohn’s disease mucosa associated with reduced inflammation. These findings identify CD161 + T reg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
| Original language | English |
|---|---|
| Journal | Nature Immunology |
| Volume | 19 |
| Issue number | 12 |
| Pages (from-to) | 1403-1414 |
| Number of pages | 12 |
| ISSN | 1529-2908 |
| DOIs | |
| Publication status | Published - 01.12.2018 |
Funding
1MRC, Centre for Transplantation, King’s College London, London, UK. 2National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK. 3Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 4Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK. 5Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. 6Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. 7Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. 8Department of Infection, Immunity and Inflammation, NIHR Leicester Respiratory Biomedical Research Unit, University of Leicester, Leicester, UK. 9Department of Medicine, Imperial College London, London, UK. 10Complement and Inflammation Research Section, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 11Institute of Cellular Medicine, Newcastle University, Newcastle, UK. 12Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA. 13National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 14These authors contributed equally: Giovanna Lombardi, Behdad Afzali. *e-mail: [email protected] The authors thank patients who contributed samples toward this study. This work was supported by the Wellcome Trust (grant 097261/Z/11/Z to B.A. and WT101159 to N.P.), the Crohn’s and Colitis Foundation of America (grant CCFA no. 3765 — CCFA genetics initiative to A.L.), British Heart Foundation (grant RG/13/12/30395 to G.L.), institutional start-up fund from Purdue University and National Heart, Lung, and Blood Institute (grant 5K22HL125593-02 to M.K.). Research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research was supported (in part) by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors thank J. O’Shea (National Institutes of Health) for his support and for providing access to ATAC-seq, the National Heart, Lung, and Blood Institute DNA Sequencing and Genomics Core for performing single-cell sequencing experiment and acknowledge the assistance of M. Arno (Genomics Centre, King’s College London) with gene expression microarray studies as well as S. Heck and R. Ellis (Biomedical Research Centre Flow Core Facility, King’s College London) for CyTOF data acquisition. In addition, the authors thank E. Mathé (Ohio State University) for critically reading the manuscript.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
