Human skin-resident CD8 T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a.

The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (T) cells, but their differentiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family transcription-factor-binding motifs in human epidermal CD8CD103CD49a T cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap between epidermal CD8CD103CD49a T cells and circulating memory CD8CD45RACD62L T cells. In vitro stimulation of circulating CD8CD45RACD62L T cells with IL-15 and TGF-β induced CD49a expression and cytotoxic transcriptional profiles in a RUNX2- and RUNX3-dependent manner. We therefore identified a reservoir of circulating cells with cytotoxic T potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8CD103CD49a T cell signature and improved patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8CD103CD49a T cells, providing immunosurveillance of infected and malignant cells.