Summary Unlike conventional T/B lymphocytes, a group of innate-like T cells, such as γδT cells and invariant NK T (iNKT) cells, preferentially reside in epithelial tissues such as the skin where they play important roles in the first line of defense to maintain the tissue integrity and, when dysregulated, also contribute to the tissue inflammatory diseases. Understanding how skin-specific localization and maintenance of innate- like T cells are regulated is critical in helping to design strategies targeting these cells for therapeutic purposes. Our preliminary studies found that iNKT cells generated in the thymus of early postnatal stages preferentially acquire a skin-homing property for their specific distribution into the skin. Considering the skin is the outmost barrier tissue exposed to foreign environments immediately after the birth of a body, we propose that the preferential generation of the skin-homing iNKT cells in the thymus are important for protection of the “border” in the infant and young and the establishment of the local immune homeostasis. In this grant application, we will dissect mechanisms regulating thymic generation of skin-homing iNKT cells and their roles in helping skin tissue development and homeostasis.