CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner

• Published in: Nature communications 2024-11, Vol.15 (1), p.9520-17, Article 9520
• Main Authors: Lo, Jonathan W., Schroeder, Jan-Hendrik, Roberts, Luke B., Mohamed, Rami, Cozzetto, Domenico, Beattie, Gordon, Omer, Omer S., Ross, Ellen M., Heuts, Frank, Jowett, Geraldine M., Read, Emily, Madgwick, Matthew, Neves, Joana F., Korcsmaros, Tamas, Jenner, Richard G., Walker, Lucy S. K., Powell, Nick, Lord, Graham M.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 38/91; 45/90; 631/250/2504/2506; 631/250/347; 64/60; 692/4020/1503/257/1389; 692/4020/1503/257/1402; 82/80; Animals; Clonal deletion; Colitis; Colitis - immunology; Colitis - microbiology; Commensalism; CTLA-4 Antigen - immunology; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytokines - metabolism; Digestive system; Disease Models, Animal; Female; Gastrointestinal Microbiome - immunology; Gastrointestinal tract; Homeostasis; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune system; Immunity, Innate; Immunity, Mucosal; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - microbiology; Intestinal microflora; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestine; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphoid cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiomes; Microbiota; Microorganisms; Mucosal immunity; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51719-6

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. At the mucosal interface of the gut and microbiome immune cells play pivotal roles to regulate between commensalism, colonisation and pathogenic invasion. Here, Lo et al. show CTLA-4 expression in innate lymphoid cells is linked to mucosal homeostasis in a microbiome dependent manner.