Itk, also known as IL-2-inducible T cell kinase, is a non-receptor tyrosine kinase of the Tec family. It is crucial for T cell receptor (TCR) signaling, playing a key role in T cell proliferation, differentiation, and the production of pro-inflammatory cytokines like IL-2, IL-4, IL-5, IL-10, and IL-13. Itk is involved in regulating signaling pathways such as those mediated by CD28, CD2, chemokine receptor CXCR4, and FcepsilonR, and is essential for actin reorganization, PLCgamma activation, calcium mobilization, and NFAT transcription factor activation in T cells [5,6,7]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, have been valuable in studying Itk.

In Itk-deficient CD4+ T cells, there is a bias against Th2 differentiation and an inability to produce Th2 cytokines in a recall response, indicating Itk's role in Th2 responses [4]. In autoimmune arthritis, ITK inhibitor treatment alleviated collagen-induced arthritis (CIA), reduced antigen-specific antibody production, interfered with Tfh cell generation, and rebalanced Th17 and Treg cells [2]. In T cell lymphomas, the development of a potent ITK degrader, BSJ-05-037, blocked TCR signaling, overcame therapeutic resistance, and increased the sensitivity of lymphoma cells to chemotherapy [3].

In conclusion, Itk is essential for T cell-related functions and cytokine production. KO/CKO mouse models have revealed its significance in Th2 responses, autoimmune arthritis, and T cell lymphomas. Targeting Itk shows potential as a therapeutic strategy for T cell-mediated diseases, including autoimmune disorders and malignancies [1,2,3,4].

References:

1. Weeks, Samuel, Harris, Rebecca, Karimi, Mobin. 2021. Targeting ITK signaling for T cell-mediated diseases. In iScience, 24, 102842. doi:10.1016/j.isci.2021.102842. https://pubmed.ncbi.nlm.nih.gov/34368657/

2. Chen, Ye, Liang, Rongzhen, Shi, Xiaoyi, Pan, Yunfeng, Zheng, Song Guo. 2023. Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 169, 115886. doi:10.1016/j.biopha.2023.115886. https://pubmed.ncbi.nlm.nih.gov/37992572/

3. Jiang, Baishan, Weinstock, David M, Donovan, Katherine A, Gray, Nathanael S, Wu, Wenchao. 2023. ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas. In Cell chemical biology, 30, 383-393.e6. doi:10.1016/j.chembiol.2023.03.007. https://pubmed.ncbi.nlm.nih.gov/37015223/

4. Kosaka, Yoko, Felices, Martin, Berg, Leslie J. 2006. Itk and Th2 responses: action but no reaction. In Trends in immunology, 27, 453-60. doi:. https://pubmed.ncbi.nlm.nih.gov/16931156/

5. Sahu, Nisebita, August, Avery. . ITK inhibitors in inflammation and immune-mediated disorders. In Current topics in medicinal chemistry, 9, 690-703. doi:. https://pubmed.ncbi.nlm.nih.gov/19689375/

6. Lo, Ho Yin. . Itk inhibitors: a patent review. In Expert opinion on therapeutic patents, 20, 459-69. doi:10.1517/13543771003674409. https://pubmed.ncbi.nlm.nih.gov/20218931/

7. Lechner, Kristina S, Neurath, Markus F, Weigmann, Benno. 2020. Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. In Journal of molecular medicine (Berlin, Germany), 98, 1385-1395. doi:10.1007/s00109-020-01958-z. https://pubmed.ncbi.nlm.nih.gov/32808093/