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

  • Beatrice Zitti
  • , Elena Hoffer
  • , Wenning Zheng
  • , Ram Vinay Pandey
  • , Heinrich Schlums
  • , Giovanna Perinetti Casoni
  • , Irene Fusi
  • , Lien Nguyen
  • , Jaanika Kärner
  • , Efthymia Kokkinou
  • , Anna Carrasco
  • , Jessica Gahm
  • , Marcus Ehrström
  • , Staffan Happaniemi
  • , Åsa V. Keita
  • , Charlotte R.H. Hedin
  • , Jenny Mjösberg
  • , Liv Eidsmo*
  • , Yenan T. Bryceson
    • *Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

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.

Original languageEnglish
JournalImmunity
Volume56
Issue number6
Pages (from-to)1285-1302.e7
ISSN1074-7613
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023

Funding

We would like to thank Nordiska Kliniken and the Division of Reconstructive Surgery, Karolinska University Hospital for excellent help in recruitment of patients and technical assistance and MedH Flow Cytometry core facility (Karolinska Institutet), supported by KI/SLL, for providing cell sorting services. This work was supported in part by funds from Novartis. We acknowledge funding from the European Union Marie Sklodowska-Curie Actions Postdoctoral Fellowship (to B.Z.), KI Foundation grant (to B.Z.), Swedish Research Council (to Y.T.B. and L.E.), Ragnar Söderberg Stiftelse, Svenska Läkaresällskapet, Stockholm County Council (ALF and Clinical Research Appointment), Psoriasisfonden, Hudfonden (to L.E.), Swedish Cancer Foundation (to Y.T.B.), Göran Gustafsson Foundation (to Y.T.B.), Stockholm City Council and Karolinska Institutet Center for Innovative Medicine (to Y.T.B.), and Wallenberg Foundation (KAW for Y.T.B. and MMW for L.E.). Conceptualization, B.Z. E.H. L.E. and Y.T.B.; methodology, B.Z. E.H. and H.S.; software, W.Z. and R.V.P.; validation, G.P.C. I.F. L.N. J.K. E.K. and A.C.; formal analyses, B.Z. E.H. W.Z. and R.V.P.; resources, L.E. J.M. J.G. M.E. S.H. Å.V.K. and C.R.H.H.; data curation, W.Z. and R.V.P.; writing – original draft, B.Z. and Y.T.B.; writing – review & editing, B.Z. E.H. L.E. and Y.T.B.; visualization, B.Z. E.H. L.E. and Y.T.B.; supervision L.E. and Y.T.B.; project administration, B.Z. L.E. and Y.T.B.; funding acquisition, B.Z. L.E. and Y.T.B. The authors declare no competing interests. We would like to thank Nordiska Kliniken and the Division of Reconstructive Surgery, Karolinska University Hospital for excellent help in recruitment of patients and technical assistance and MedH Flow Cytometry core facility (Karolinska Institutet), supported by KI/SLL, for providing cell sorting services. This work was supported in part by funds from Novartis . We acknowledge funding from the European Union Marie Sklodowska-Curie Actions Postdoctoral Fellowship (to B.Z.), KI Foundation grant (to B.Z.), Swedish Research Council (to Y.T.B. and L.E.), Ragnar Söderberg Stiftelse , Svenska Läkaresällskapet , Stockholm County Council (ALF and Clinical Research Appointment), Psoriasisfonden, Hudfonden (to L.E.), Swedish Cancer Foundation (to Y.T.B.), Göran Gustafsson Foundation (to Y.T.B.), Stockholm City Council and Karolinska Institutet Center for Innovative Medicine (to Y.T.B.), and Wallenberg Foundation ( KAW for Y.T.B. and MMW for L.E.).

Keywords

  • adaptive immunity
  • CD69
  • cytotoxicity
  • differentiation
  • epigenetic
  • integrin αβ
  • melanoma
  • skin
  • tissue-resident memory cells

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