CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner
Abstract 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. Checkpoin...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-51719-6 |
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| author | Jonathan W. Lo Jan-Hendrik Schroeder Luke B. Roberts Rami Mohamed Domenico Cozzetto Gordon Beattie Omer S. Omer Ellen M. Ross Frank Heuts Geraldine M. Jowett Emily Read Matthew Madgwick Joana F. Neves Tamas Korcsmaros Richard G. Jenner Lucy S. K. Walker Nick Powell Graham M. Lord |
| author_facet | Jonathan W. Lo Jan-Hendrik Schroeder Luke B. Roberts Rami Mohamed Domenico Cozzetto Gordon Beattie Omer S. Omer Ellen M. Ross Frank Heuts Geraldine M. Jowett Emily Read Matthew Madgwick Joana F. Neves Tamas Korcsmaros Richard G. Jenner Lucy S. K. Walker Nick Powell Graham M. Lord |
| author_sort | Jonathan W. Lo |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9c1706884f1e46cd8fa10a092e27a500 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9c1706884f1e46cd8fa10a092e27a5002024-11-10T12:32:18ZengNature PortfolioNature Communications2041-17232024-11-0115111710.1038/s41467-024-51719-6CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent mannerJonathan W. Lo0Jan-Hendrik Schroeder1Luke B. Roberts2Rami Mohamed3Domenico Cozzetto4Gordon Beattie5Omer S. Omer6Ellen M. Ross7Frank Heuts8Geraldine M. Jowett9Emily Read10Matthew Madgwick11Joana F. Neves12Tamas Korcsmaros13Richard G. Jenner14Lucy S. K. Walker15Nick Powell16Graham M. Lord17Division of Digestive Diseases, Faculty of Medicine, Imperial College LondonSchool of Immunology and Microbial Sciences, King’s College LondonSchool of Immunology and Microbial Sciences, King’s College LondonSchool of Immunology and Microbial Sciences, King’s College LondonDivision of Digestive Diseases, Faculty of Medicine, Imperial College LondonCRUK City of London Centre Single Cell Genomics Facility, UCL Cancer Institute, University College LondonSchool of Immunology and Microbial Sciences, King’s College LondonInstitute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free CampusInstitute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free CampusCentre for Host-Microbiome Interactions, King’s College LondonCentre for Host-Microbiome Interactions, King’s College LondonDivision of Digestive Diseases, Faculty of Medicine, Imperial College LondonCentre for Host-Microbiome Interactions, King’s College LondonDivision of Digestive Diseases, Faculty of Medicine, Imperial College LondonUCL Cancer Institute and CRUK City of London Centre, University College LondonInstitute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free CampusDivision of Digestive Diseases, Faculty of Medicine, Imperial College LondonSchool of Immunology and Microbial Sciences, King’s College LondonAbstract 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.https://doi.org/10.1038/s41467-024-51719-6 |
| spellingShingle | Jonathan W. Lo Jan-Hendrik Schroeder Luke B. Roberts Rami Mohamed Domenico Cozzetto Gordon Beattie Omer S. Omer Ellen M. Ross Frank Heuts Geraldine M. Jowett Emily Read Matthew Madgwick Joana F. Neves Tamas Korcsmaros Richard G. Jenner Lucy S. K. Walker Nick Powell Graham M. Lord CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner Nature Communications |
| title | CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| title_full | CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| title_fullStr | CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| title_full_unstemmed | CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| title_short | CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| title_sort | ctla 4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner |
| url | https://doi.org/10.1038/s41467-024-51719-6 |
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