Absence of Tec Family Kinases Interleukin-2 Inducible T cell Kinase (Itk) and Bruton's Tyrosine Kinase (Btk) Severely Impairs FcϵRI-dependent Mast Cell Responses

Abstract

Here we investigate the role of Tec kinases, Itk, and Btk as modulators of these processes. Itk is activated in mast cells upon Fc⑀RI-mediated signaling and Itk Ϫ/Ϫ mice have been reported to display decreased mast cell degranulation and histamine release in vivo (2, 4). However, our analysis of Itk-null mast cells revealed that the absence of Itk does not intrinsically affect mast cell degranulation either in vitro or in vivo (5). Although Itk is critical for TCR-mediated induction of intracellular Ca 2ϩ mobilization and Erk activation, Itk is not required for intracellular calcium signaling in response to Fc⑀RI-mediated signaling in mast cells, and Itkdeficient mast cells secrete elevated cytokines upon activation(5). Collectively, these data strongly suggests that Itk has cell type-specific functions.In mast cells, Btk is activated by the Fc⑀RI, c-Kit, and IL-3 receptors (6 -8). Its function has been well studied in B cells where it is activated downstream of the BCR (9, 10). Loss of Btk function in humans causes X-linked agammaglobulinemia (XLA), a condition where patients do not have sufficient immunoglobulins, with a milder phenotype observed in Btk-deficient mice (11,12). Mast cell development appears normal in the absence of Btk, both in vivo and in vitro. However, more bone marrow-derived mast cells (BMMCs) cells are produced from Btk-deficient mice in response to IL-3 (7). Btk Ϫ/Ϫ BMMCs also exhibit mild to moderate impairment of early and late Fc⑀RI-mediated responses such as degranulation, histamine release, * This work was supported, in whole or in part, by National Institutes of Health Grants AI051626 and AI065566 (to A. A.), and AI051626-S1 (to A. A.) (for J. L. M. BMMCs, bone marrow-derived mast cells; Bmx, bone marrow kinase on X-chromosome; Btk, Bruton's tyrosine kinase; Itk, interleukin-2 inducible T cell kinase; SAPK/JNK, stress-activated protein kinase/c-Jun N-terminal kinase; NFATc1, nuclear factor of activated T-cells cytoplasmic 1; Rlk, resting lymphocyte kinase; Syk, spleen tyrosine kinase; Tec, tyrosine kinase expressed in hepatocellular carcinoma; Txk, T and X cell-expressed kinase; XLA, X-linked agammaglobulinemia.

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…Moreover, our studies using the RBL-2H3 mast cell line demonstrated no effects of PRN694 on FcR⑀-induced activation, indicating that myeloid-derived immune cells are not uniquely dependent upon RLK and ITK. This concept is supported by recent literature indicating that BTK is a dominant regulator of mast cell FcR⑀ degranulation and that ITK plays an accessory role, and only combined genetic ablation can eliminate degranulation (57). Notably, however, we did not observe significant expression of ITK in our RBL-2H3 cell line, indicating some potential molecular differences that warrant further study (58).…”

Mediators Released During Human Anaphylaxis

“…Another Src family kinase, Fgr, has been shown to be critical for activation of mast cells and IgE-mediated anaphylaxis in mice, as Fgr positively regulates degranulation, production of eicosanoids, and cytokines [65]. In addition, the absence of a number of Tec family kinases severely impairs FcεRI-dependent mast cell responses [66].…”

Targets for Ibrutinib Beyond B Cell Malignancies

“…Interestingly, compensatory pathways were described for BTK and TEC as well as for BTK and ITK in mast cells 66, 67, which will be described in more detail in the next sections of this review.…”