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 Omer, Ellen M. Ross, Frank Heuts, Geraldine M. Jowett, Emily Read, Matthew Madgwick, Joana F. Neves, Tamás Korcsmáros, Richard G. Jenner, Lucy S. K. Walker, Nick Powell, Graham M. Lord
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.