Tec family kinases Itk and Rlk / Txk in T lymphocytes: cross‐regulation of cytokine production and T‐cell fates

Abstract

Developing thymocytes and T cells express the Tec kinases Itk, Rlk/Txk and Tec, which are critical modulators of T‐cell receptor signaling, required for full activation of phospholipase Cγ, and downstream Ca2+ and ERK‐mediated signaling pathways. Over the last 10 years, data have implicated the Tec family kinases Itk and Rlk/Txk as important regulators of cytokine production by CD4+ effector T‐cell populations. Emerging data now suggest that the Tec family kinases not only influence cytokine‐producing T‐cell populations in the periphery, but also regulate the development of distinct innate‐type cytokine‐producing T‐cell populations in the thymus. Together, these results suggest that the Tec family kinases play critical roles in helping shape immune responses via their effects on the differentiation and function of distinct cytokine‐producing, effector T‐cell populations.

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

“…The development of cGVHD in this model was not effectively constrained by 10 mg/kg/d cyclosporine therapy that is T cell immune suppressive (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/ JCI75328DS1). Histology of representative skin lesions obtained vation of NF-κB, MAPK, and nuclear factor of activated T cells (NFAT) in lymphocytes, resulting in cellular activation, release of soluble effector molecules, and rapid proliferation (18). Antibody production by B cells hinges upon the function of BTK (17).…”

“…While XID and Itk -/-mice are useful in exploring the mechanisms responsible for cGVHD generation, there are caveats. For instance, TEC kinase has been shown to compensate for the lack of BTK in the XID mouse model, and complete genetic ablation of ITK blunts thymic maturation of functionally mature T lymphocytes (18,41,42). As a result, we can conclude that ITK and BTK are necessary components for the development of cGVHD; however, we cannot (C) Splenocytes were purified from transplanted mice on day 60, and frequency of GC B cells was quantified.…”

Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

“…3 Upon TCR ligation in Th1 and CD8 T cells, ITK and redundant resting lymphocyte kinase (RLK or TXK) activate phospholipase Cg (PLCg), launching a signaling cascade that includes the nuclear factor of activated T cells (NFAT), nuclear factor kB, and mitogen-activated protein kinase pathways, resulting in cellular activation, cytokine release, and rapid proliferation. 4 In cancer, ITK is a critical signaling motif important to acute lymphoblastic T-cell leukemia and Sézary syndrome/cutaneous T-cell lymphoma due to aberrant activation and heightened expression. 5 In healthy Th1-polarized and CD8 effector cells, ITK plays a supportive yet dispensable role to RLK.…”

Emerging protein kinase inhibitors for the treatment of non-Hodgkin’s lymphoma

“…The effect of ibrutinib is thought to be mediated largely through Btk inhibition, but recently a second immune mechanism, inhibition of IL-2 inducible kinase (ITK), has been proposed [127]. In the Th1 immune response after T-cell receptor activation, ITK and redundant resting lymphocyte kinase promote cytotoxic signal though PLC g [128,129]. The Th2 immune response enhances B-cell antibody formation and interferes with cytotoxic effects.…”