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

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 () and Graham M. Lord ()
Additional contact information
Jonathan W. Lo: Imperial College London
Jan-Hendrik Schroeder: King’s College London
Luke B. Roberts: King’s College London
Rami Mohamed: King’s College London
Domenico Cozzetto: Imperial College London
Gordon Beattie: University College London
Omer S. Omer: King’s College London
Ellen M. Ross: Royal Free Campus
Frank Heuts: Royal Free Campus
Geraldine M. Jowett: King’s College London
Emily Read: King’s College London
Matthew Madgwick: Imperial College London
Joana F. Neves: King’s College London
Tamas Korcsmaros: Imperial College London
Richard G. Jenner: University College London
Lucy S. K. Walker: Royal Free Campus
Nick Powell: Imperial College London
Graham M. Lord: King’s College London

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51719-6

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