The TEC-family protein tyrosine kinases ITK, RLK and TEC have been identified as key components of T-cell-receptor signalling that contribute to the regulation of phospholipase C-gamma, the mobilization of Ca(2+) and the activation of mitogen-activated protein kinases. Recent data also show that TEC kinases contribute to T-cell-receptor-driven actin reorganization and cell polarization, which are required for productive T-cell activation. Functional studies have implicated TEC kinases as important mediators of pathways that control the differentiation of CD4(+) T helper cells. Here, we review studies of signalling pathways that involve TEC kinases and how these pathways might contribute to the regulation of T-helper-cell differentiation and function.

Mammalian TOR (mTOR) regulates cell growth, proliferation, and migration. Because mTOR knock-outs are embryonic lethal, we generated a viable hypomorphic mouse by neo-insertion that partially disrupts mTOR transcription and creates a potential physiologic model of mTORC1/ TORC2 inhibition. Homozygous knock-in mice exhibited reductions in body, organ, and cell size. Although reductions in most organ sizes were proportional to decreased body weight, spleens were disproportionately smaller. Decreases in the total number of T cells, particularly memory cells, and reduced responses to chemokines suggested alterations in T-cell homing/homeostasis. T-cell receptor-stimulated T cells proliferated less, produced lower cytokine levels, and expressed FoxP3. Decreased neutrophil numbers were also observed in the spleen, despite normal development and migration in the bone marrow. However, B-cell effects were most pronounced, with a partial block in B-cell development in the bone marrow, altered splenic populations, and decreases in proliferation, antibody production, and migration to chemokines. Moreover, increased AKT Ser473 phosphorylation was observed in activated B cells, reminiscent of cancers treated with rapamycin, and was reduced by a DNA-pk inhibitor. Thus, mTOR is required for the maturation and differentiation of multiple immune cell lineages. These mice provide a novel platform for studying the consequences of constitutively reduced mTORC1/TORC2 activity. IntroductionThe mammalian target of rapamycin (mTOR) is part of a conserved pathway regulating fundamental physiologic functions, including nutrient sensing and metabolism, and cell growth, proliferation, and migration. mTOR forms 2 protein complexes: one with RAPTOR, mLST8(G␤L), and PRAS40 to form TOR complex 1 (mTORC1) involved in phosphorylating S6K and 4EBP1, 1,2 and a second with RICTOR, mLST8(G␤L), SIN1, and PROTOR to form TOR complex 2 (mTORC2), which phosphorylates AKT on Ser473. [2][3][4] In yeast, TOR controls cell proliferation and size. 5,6 In Drosophila, inactivation of dTOR results in lethality and reduced embryo size. 7,8 Genetically targeting the kinase domain of murine mTOR for inactivation results in embryonic lethality, 9-11 although deletions in the C terminal portion yield mice that are normal and fertile. 11 ENU-mutagenesis screens uncovered an additional embryonic lethal mutation of mTOR, resulting in flat-top embryos lacking telencephalons resulting from limited neuroectodermal cell proliferation. 10,12 Knockouts of Raptor or Sin1 13 result in early embryonic lethality, whereas those of Rictor and mLST8(G␤L) lead to late embryonic lethality and defective vascular development. mTOR signaling/function has been deduced from studies with rapamycin, which associates with FKBP12, 14 and together binds mTOR to destabilize mTORC1. Although originally thought to affect only mTORC1, long-term treatment with rapamycin can also affect mTORC2. 15 Rapamycin and numerous rapalogs are potent immunosuppressants used in cancer chemotherapy and bone marro...

Summary The Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of non-receptor tyrosine kinases consists of five members: Tec, Btk (Bruton’s tyrosine kinase), Itk (inducible T-cell kinase), Rlk/Txk (resting lymphocyte kinase), and Bmx/Etk (bone marrow-expressed kinase). Although their functions are probably best understood in antigen receptor signaling, where they participate in the phosphorylation and regulation of phospholipase C-γ (PLC-γ), it is now appreciated that these kinases contribute to signaling from many receptors and that they participate in multiple downstream pathways, including regulation of the actin cytoskeleton. In T cells, three Tec kinases are expressed, Itk, Rlk/Txk, and Tec. Itk is expressed at highest amounts and plays the major role in regulating signaling from the T-cell receptor (TCR). Recent studies provide evidence that these kinases contribute to multiple aspects of T-cell biology and have unique roles in T-cell development that have revealed new insight into the regulation of conventional and innate T-cell development. We review new findings on the Tec kinases with a focus on their roles in T-cell development and mature T-cell differentiation.