Gastroenterology · 2026
TIM3 Signaling in Effector T Cells Acts as an Immunometabolic Switch in the Purine Degradation Pathway to Suppress Intestinal Inflammation.
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Knauss Annkathrin, Gabel Michael, Kaufmann Cora, Loges Laura, Rath Timo, Atreya Raja, Radtke Daniel, Grapp Hendrik, Gerlach Katharina, Thoma Oana-Maria, Eckstein Markus, Gessner Arne, Bartels Nora, Schmid Benjamin, Tripal Philipp, Weigmann Benno, Neurath Markus F
Аннотация
BACKGROUND & AIMS: Effector T lymphocytes have been found to play a key role in inflammatory bowel diseases (IBDs). 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 signaling in IBDs.
METHODS: We combined experimental colitis models in TIM3-deficient mice with analyses of human IBDs and control samples. Blood and mucosal T cells were assessed using multicolor flow cytometry, cytokine profiling, and untargeted metabolomics. Single-cell sequencing data were analyzed. The TIM3 ligand Gal-9 was used to study TIM3 function.
RESULTS: TIM3 expression was higher on blood T-helper cells (Th) type 1 and mucosal Th17 cells in patients with IBD compared with 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 ADA and the purine degradation pathway to keep effector T cells in an exhausted PD1+ state. However, insufficient availability of the TIM3 ligand Gal-9 limited effective TIM3 signaling in chronic inflammation. Treatment with Gal-9 ameliorated experimental colitis via ADA inhibition. Moreover, in IBD T cells, Gal-9 induced an immunometabolic switch associated with reduction of terminally exhausted Th17 cells.
CONCLUSIONS: TIM3 plays a key role in the immunometabolism of effector T cells in colitis by suppressing ADA 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.
METHODS: We combined experimental colitis models in TIM3-deficient mice with analyses of human IBDs and control samples. Blood and mucosal T cells were assessed using multicolor flow cytometry, cytokine profiling, and untargeted metabolomics. Single-cell sequencing data were analyzed. The TIM3 ligand Gal-9 was used to study TIM3 function.
RESULTS: TIM3 expression was higher on blood T-helper cells (Th) type 1 and mucosal Th17 cells in patients with IBD compared with 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 ADA and the purine degradation pathway to keep effector T cells in an exhausted PD1+ state. However, insufficient availability of the TIM3 ligand Gal-9 limited effective TIM3 signaling in chronic inflammation. Treatment with Gal-9 ameliorated experimental colitis via ADA inhibition. Moreover, in IBD T cells, Gal-9 induced an immunometabolic switch associated with reduction of terminally exhausted Th17 cells.
CONCLUSIONS: TIM3 plays a key role in the immunometabolism of effector T cells in colitis by suppressing ADA 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.