TIM3 signaling in effector T cells acts as an immunometabolic switch in the purine degradation pathway to suppress intestinal inflammation.

Abstract

Effector T lymphocytes have been shown to play a key role in inflammatory bowel diseases (IBD). However, the molecular pathways controlling their metabolism and functional activity remain poorly defined. We aimed to elucidate the role of the immune checkpoint receptor TIM3 for T cell signalling in IBD. We combined experimental colitis models in TIM3-deficient mice with analyses of human IBD and control samples. Blood and mucosal T cells were assessed using multi-colour flow cytometry, cytokine profiling, and untargeted metabolomics. Single-cell sequencing data were analysed. The TIM3 ligand galectin-9 was used to study TIM3 function. TIM3 expression was higher on blood Th1 cells and mucosal Th17 cells in IBD patients compared to controls, with levels being particularly high in anti-TNF refractory patients. Mice lacking TIM3 showed exacerbated oxazolone colitis and increased effector T cell activation. Metabolome profiling and functional analyses revealed that TIM3 signaling functions as an immunometabolic regulator, suppressing adenosine deaminase and the purine degradation pathway to keep effector T cells in an exhausted PD1+ state. However, insufficient availability of the TIM3 ligand galectin-9 limited effective TIM3 signalling in chronic inflammation. Treatment with galectin-9 ameliorated experimental colitis via adenosine deaminase inhibition. Moreover, in IBD T cells, galectin-9 induced an immunometabolic switch associated with reduction of terminally exhausted Th17 cells. TIM3 plays a key role in the immunometabolism of effector T cells in colitis by suppressing adenosine deaminase and the purine degradation pathway. Targeting the immunometabolic functions of effector T cells via TIM3 activation emerges as a promising strategy for chronic intestinal inflammation.