Cutting edge: Intrinsic programming of thymic γδT cells for specific peripheral tissue localization

Various innate-like T cell subsets preferentially reside in specific epithelial tissues as the first line of defense. However, mechanisms regulating their tissue-specific development are poorly understood. Using the prototypical skin intraepithelial γδT cells (sIELs) as a model, we show in this study that a TCR-mediated selection plays an important role in promoting acquisition of a specific skin-homing property by fetal thymic sIEL precursors for their epidermal location, and the skin-homing potential is intrinsically programmed even before the selection. In addition, once localized in the skin, the sIEL precursors develop into sIELs without the requirement of further TCR-ligand interaction. These studies reveal that development of the tissue-specific lymphocytes is a hard-wired process that targets them to specific tissues for proper functions.