Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis

Kristina Lechner (1) , Stefanie Mott (1) , Ragheed Al-Saifi , Lisa Knipfer (1) , Stefan Wirtz , Raja Atreya , Michael Vieth (1) , Timo Rath (1) , Tina Fraass , Zoltan Winter , Avery August (2) , Jeremy Luban (3) , Valérie Zimmermann (4) , Benno Weigmann (1) , Markus Neurath (1)

1 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
2 Cornell University [New York]
3 UMASS - University of Massachusetts Medical School [Worcester]
4 Hematopoïèse et Immunothérapie

Background & Aims: The molecular checkpoints driving T cell activation and cytokine responses in ulcerative colitis are incompletely understood. Here, we studied the Tec kinase ITK in ulcerative colitis and explored the link between Cyclosporine A (CsA) function and ITK activation. Methods: We analyzed patients with inflammatory bowel disease (n=202) and evaluated ITK expression and activity as well as the functional effects of CsA. Moreover, three independent murine colitis models were used to investigate the functional role of ITK. Finally, the activity of ITK was blocked via pharmacological inhibitors and genetically engineered mice. Readout parameters were mini-endoscopy, histopathology, mucosal T cell apoptosis and cytokine production. Results: We found an expansion of ITK expressing mucosal CD4+ T cells in ulcerative colitis rather than Crohn ́s disease that correlated with disease severity. CsA suppressed activation of ITK in cultured CD4+ T cells and calcineurin-containing microclusters adjacent to the T cell receptor signaling complex. Functionally, the capacity of CsA to suppress activity of experimental colitis was critically dependent on ITK. Moreover, genetic inactivation of Itk via gene targeting or induction of allele- sensitive Itk mutants suppressed experimental colitis in three colitis models, while pharmacological ITK blockers could be used for treatment of established colitis and triggered resolution of inflammation. Hereby, ITK controlled apoptosis and activation of mucosal Th2 and Th17 lymphocytes via NFATc2 signaling pathways. Conclusion: ITK activation was detected in ulcerative colitis and could be downregulated in cultured T cells by CsA administration. Selective targeting of ITK emerges as an attractive approach for treatment of chronic intestinal inflammation and potentially ulcerative colitis by driving resolution of mucosal inflammation

Mots clés: Cyclosporine A; Cytokines; IBD; ITK; Therapeutic Strategies

Domaines: Biologie cellulaire

Kristina Lechner, Stefanie Mott, Ragheed Al-Saifi, Lisa Knipfer, Stefan Wirtz, et al.. Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis. Gastroenterology, 2021, 161 (4), pp.1270-1287.e19. ⟨10.1053/j.gastro.2021.06.072⟩. ⟨hal-03359328⟩