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 (TRM) cells, but their differen-tiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family tran-scription-factor-binding motifs in human epidermal CD8+CD103+CD49a+ TRM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap be-tween epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. In vitro stimulation of circulating CD8+CD45RA-CD62L+ T cells with IL-15 and TGF-b induced CD49a expres-sion and cytotoxic transcriptional profiles in a RUNX2-and RUNX3-dependent manner. We therefore identi-fied a reservoir of circulating cells with cytotoxic TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved pa-tient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differ-entiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malig-nant cells.

Automated summary

The integrin CD49a is a marker for highly cytotoxic epidermal-tissue-resident memory (TRM) cells, with enrichment of RUNT family transcription-factor-binding motifs and high expression of RUNX2 and RUNX3 proteins. Clonal overlap was observed between epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. Stimulation of circulating T cells induced CD49a expression and cytotoxic profiles in a RUNX2- and RUNX3-dependent manner. In melanoma patients, high RUNX2 transcription correlated with a cytotoxic TRM cell signature and improved patient survival. These findings suggest that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic TRM cells, providing immune surveillance against infected and malignant cells.