The developmental pathway for [CD103.sup.+][CD8.sup.+] tissue-resident memory t cells of skin

Tissue-resident memory T cells ([T.sub.RM] cells) provide superior protection against infection in extralymphoid tissues. Here we found that [CD103.sup.+][CD8.sup.+] [T.sub.RM] cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL- 15) and transforming growth factor-b (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into [T.sub.RM] cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.