Lo, Jonathan W;
Schroeder, Jan-Hendrik;
Roberts, Luke B;
Mohamed, Rami;
Cozzetto, Domenico;
Beattie, Gordon;
Omer, Omer S;
... Lord, Graham M; + view all
(2024)
CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner.
Nature Communications
, 15
(1)
, Article 9520. 10.1038/s41467-024-51719-6.
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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.
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