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

Lechner-Grimm K, Mott S, Al-Saifi R, Knipfer L, Wirtz S, Atreya R, Vieth M, Rath T, Fraass T, Winter Z, August A, Luban J, Zimmermann VS, Weigmann B, Neurath M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Gastroenterology Elsevier

DOI: 10.1053/j.gastro.2021.06.072

Abstract

Background & Aims: The molecular checkpoints driving T cell activation and cytokine responses in ulcerative colitis (UC) are incompletely understood. Here, we studied the Tec kinase ITK in UC. Methods: We analyzed patients with inflammatory bowel disease (n = 223) and evaluated ITK activity as well as the functional effects of cyclosporine-A (CsA). In addition, 3 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 pITK-expressing mucosal CD4+ T cells in UC 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. Genetic inactivation of Itk via gene targeting or induction of allele-sensitive Itk mutants prevented experimental colitis in 3 colitis models, and treatment with pharmacological ITK blockers suppressed established colitis. In addition, ITK controlled apoptosis and activation of mucosal Th2 and Th17 lymphocytes via NFATc2 signaling pathways. Conclusions: ITK activation was detected in UC and could be down-regulated in cultured T cells by CsA administration. Selective targeting of ITK emerges as an attractive approach for treatment of chronic intestinal inflammation and potentially UC by driving resolution of mucosal inflammation.

Authors with CRIS profile

Kristina Lechner-Grimm Lehrstuhl für Genetik Lisa Knipfer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Michael Vieth Professur für Allgemeine Pathologie Timo Rath Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Benno Weigmann Medizinische Fakultät Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1)

Related research project(s)

None - None

Involved external institutions

Cornell University US United States (USA) (US) University of Massachusetts Medical School US United States (USA) (US) University of Montpellier / Université Montpellier FR France (FR)

How to cite

APA:

Lechner-Grimm, K., Mott, S., Al-Saifi, R., Knipfer, L., Wirtz, S., Atreya, R.,... Neurath, M. (2021). Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis. Gastroenterology. https://doi.org/10.1053/j.gastro.2021.06.072

MLA:

Lechner-Grimm, Kristina, 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).

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