Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis
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REVIEW
Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis Kristina S. Lechner 1 & Markus F. Neurath 1,2,3 & Benno Weigmann 1,4 Received: 29 January 2020 / Revised: 10 July 2020 / Accepted: 4 August 2020 # The Author(s) 2020
Abstract ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development. Keywords ITK . Autoimmune diseases . Cancer . Inhibitor
Introduction ITK was first reported in the late 1980s and early 1990s when it was first cloned [1–5]. The name of ITK originates from the finding that its expression was induced by the administration of IL-2 in IL-2-deprived cells [1]. This protein is also named Emt [2, 5] and Tsk [3] and belongs to the Tec family of nonreceptor tyrosine kinases (TFK) [6]. Besides ITK, the TFK consists of four other members namely Btk (Bruton’s tyrosine kinase), Tec, Rlk (also known as Txk) and Bmx [6]. While Btk is mainly expressed in B lymphocytes [7], ITK, alongside
* Benno Weigmann [email protected] 1
Department of Medicine 1, Kussmaul Campus for Medical Research, University of Erlangen-Nürnberg, Hartmannstr.14, 91052 Erlangen, Germany
2
Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
3
Ludwig Demling Endoscopy Center of Excellence, Ulmenweg 18, 91054 Erlangen, Germany
4
Medical Immunology Campus Erlangen, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, 91052 Erlangen, Germany
with Rlk and Tec, is preferentially expressed in T lymphocytes whereas ITK shows the highest level of expression [1–3, 8]. Apart from that, ITK is also expressed in mast cells [9], natural killer cells [10] and invariant natural killer T cells (iNKT) [11]. Since up to date only ITK has been found to have a defined function in the T cell lineage, this kinase is considered to be the predominant Tec kinase in T cells [9]. The domain structure of ITK and members of the TFK in general reveals unique features and also features shared with kinases belonging to the Src family kinases. ITK consists of an
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