The Tec Kinase ITK Regulates Thymic Expansion, Emigration, and Maturation of gamma delta 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-/- mice have spontaneously elevated serum IgE levels, resulting from an expansion of the V gamma 1.1+V delta 6.3+ subset of gamma delta T cells, known as gamma delta NKT cells. Comparisons between gamma delta NKT cells and alpha beta 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 gamma delta 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 gamma delta NKT cells plus a heterogeneous population of V gamma 1.1+V delta 6.3+ 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-/- gamma delta 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 gamma delta NKT cells in the adult thymus, to block their emigration, and to promote terminal NKT cell maturation.