The Tec Kinase ITK Regulates Thymic Expansion, Emigration, and Maturation of gd NKT Cells

The Tec family tyrosine kinase, Itk, regulates signaling downstream of the TCR. The absence of Itk in CD4 + T cells results in impaired Th2 responses along with defects in maturation, cytokine production, and survival of iNKT cells. Paradoxically, Itk 2/2 mice have spontaneously elevated serum IgE levels, resulting from an expansion of the Vg1.1 + Vd6.3 + subset of gd T cells, known as gd NKT cells. Comparisons between gd NKT cells and ab iNKT cells showed convergence in the pattern of cell surface marker expression, cytokine profiles, and gene expression, suggesting that these two subsets of NKT cells undergo similar differentiation programs. Hepatic gd NKT cells have an invariant TCR and are derived predominantly from fetal progenitors that expand in the thymus during the first weeks of life. The adult thymus contains these invariant gd NKT cells plus a heterogeneous population of Vg1.1 + Vd6.3 + T cells with diverse CDR3 sequences. This latter population, normally excluded from the liver, escapes the thymus and homes to the liver when Itk is absent. In addition, Itk 2/2 gd NKT cells persistently express high levels of Zbtb16 (PLZF) and Il4, genes that are normally downregulated in the most mature subsets of NKT cells. These data indicate that Itk signaling is required to prevent the expansion of gd NKT cells in the adult thymus, to block their emigration, and to promote terminal NKT cell maturation. T he Tec family tyrosine kinase, Itk, regulates signal trans-duction in T cells via the TCR. In the absence of Itk, T cells have defects in phospholipase C-g1 activation, calcium mobilization, MAPK phosphorylation, and AP-1 and NFAT activation following stimulation (1). As a consequence, Itk plays a critical role in ab T cell development, influencing both positive and negative selection. During thymic development, conventional CD4 + and CD8 + T cells are the predominant populations that arise. These cells develop with a naive phenotype (CD62L hi /CD44 lo) and require a lengthy process of activation, proliferation, and differentiation prior to exhibiting effector cell characteristics (2–5). In contrast, thymic development in Itk 2/2 mice produces populations of both CD4 + and CD8 + T cells that resemble memory cells and exhibit innate effector functions (6–9). Thus, TCR signaling via Itk does not simply regulate the efficiency of conventional CD4 + and CD8 + T cell maturation but also maintains the appropriate balance of naive versus innate T …