Differential roles of IL-2-inducible T cell kinase-mediated TCR signals in tissue-specific localization and maintenance of skin intraepithelial T cells

Tissue-specific innate-like γδ T cells are important components of the immune system critical for the first line of defense, but mechanisms underlying their tissue-specific development are poorly understood. Our study with prototypical skin-specific intra-epithelial γδT lymphocytes (sIELs) found that among different thymic γδ T cell subsets fetal thymic precursors of sIELs specifically acquire a unique skin-homing property after positive selection, suggesting an important role of the TCR selection signaling in "programming" them for tissue-specific development. In this study, we identified IL-2-inducible T cell kinase (ITK) as a critical signal molecule regulating the acquirement of the skin-homing property by the fetal thymic sIEL precursors. In ITK knockout mice, the sIEL precursors could not undergo positive selection-associated upregulation of thymus-exiting and skin-homing molecules sphingosine-1-phosphate receptor 1 and CCR10 and accumulated in the thymus. However, the survival and expansion of sIELs in the skin did not require ITK-transduced TCR signaling, whereas its persistent activation impaired sIEL development by inducing apoptosis. These findings provide insights into molecular mechanisms underlying differential requirements of TCR signaling in peripheral localization and maintenance of the tissue-specific T cells.