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

Immunity. 2023 Jun 13;56(6):1285-1302.e7. doi: 10.1016/j.immuni.2023.05.003. Epub 2023 Jun 2.


The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (TRM) cells, but their differentiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family transcription-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 between 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-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 TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malignant cells.

Keywords: CD69; adaptive immunity; cytotoxicity; differentiation; epigenetic; integrin α(1)β(1); integrin α(E)β(7); melanoma; skin; tissue-resident memory cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes* / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Humans
  • Immunologic Memory
  • Integrin alpha1 / metabolism
  • Integrins / metabolism
  • Leukocyte Common Antigens / metabolism
  • Melanoma* / metabolism


  • Integrin alpha1
  • Integrins
  • Core Binding Factor Alpha 1 Subunit
  • Leukocyte Common Antigens
  • RUNX2 protein, human