CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner
The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.
Authors
- Gordon Beattie
- Tamás Korcsmáros (ORCID: https://orcid.org/0000-0003-1717-996X)
- Frank Heuts (ORCID: https://orcid.org/0000-0002-7349-2128)
- Graham M. Lord (ORCID: https://orcid.org/0000-0003-2069-4743)
- Jonathan W. Lo (ORCID: https://orcid.org/0000-0002-2514-9333)
- Matthew Madgwick (ORCID: https://orcid.org/0000-0002-7901-416X)
- Luke B. Roberts (ORCID: https://orcid.org/0000-0003-1143-304X)
- Lucy S. K. Walker (ORCID: https://orcid.org/0000-0001-5986-5015)
- Emily Read (ORCID: https://orcid.org/0000-0002-0376-2989)
- Nick Powell (ORCID: https://orcid.org/0000-0003-3231-6950)
- Jan-Hendrik Schroeder (ORCID: https://orcid.org/0000-0001-5114-4918)
- Richard G. Jenner (ORCID: https://orcid.org/0000-0002-2946-6811)
- Joana F. Neves (ORCID: https://orcid.org/0000-0001-5842-4162)
- Ellen M. Ross (ORCID: https://orcid.org/0000-0001-9249-1043)
- Domenico Cozzetto (ORCID: https://orcid.org/0000-0001-6752-5432)
- Geraldine M. Jowett (ORCID: https://orcid.org/0000-0002-8436-6637)
- Rami Mohamed
- Omer Omer
Institutions
- King's College London (GB)
- Norwich Research Park (GB)
- Manchester Academic Health Science Centre (GB)
- The Royal Free Hospital (GB)
- University of Manchester (GB)
- Quadram Institute (GB)
- Earlham Institute (GB)
- King's College School (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1038/s41467-024-51719-6
- Citations
- 12
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.89
Funders
- Wellcome
- Wellcome Trust
- Sunnybrook Research Institute
- UK Research and Innovation
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Research Councils UK
- Imperial College London
- King's College London
- University of Toronto
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- St. George's, University of London