Letter | Published:

Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours

Nature volume 552, pages 253257 (14 December 2017) | Download Citation

  • An Erratum to this article was published on 10 January 2018

This article has been updated


Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses1,2. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

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Change history

  • 10 January 2018

    Please see accompanying Erratum (http://doi.org/10.1038/nature25445). The words ‘infection with’ were missing from the sentence ‘Furthermore, Runx3 RNAi also impaired TRM cell differentiation in the context of a localized infection with enteric Listeria monocytogenes expressing GP33–41 (LM–GP33–41) (Fig. 2b).’ In Fig. 1a, in the x-axis label of bottom right graph ‘D35 kid/D35 TCM’ was changed to ‘D7 kid/D7 TCM’. In Fig. 1e, the arrow pointing from the spleen to TCM should have moved to the left, and in Fig. 1f ‘Irf4’ was wrongly set in italic font. These errors have been corrected online. See Supplementary Information to the Erratum for the original Fig. 1


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We thank all the members of the Goldrath and Pipkin laboratories for their contributions. We also thank the Flow Cytometry Core at the La Jolla Institute for Allergy and Immunology. This study was funded in part by the UCSD Molecular Biology Cancer Fellowship (J.J.M.), the US National Institutes of Health U19AI109976 (S.C., M.E.P., A.W.G) and R01 AI095634 (M.E.P.), California Institute for Regenerative Medicine RB5-07012 (W.W.), the Kimmelman Family Foundation and the San Diego Center for Precision Immunotherapy (A.W.G.).

Author information

Author notes

    • Clara Toma
    •  & Bingfei Yu

    These authors contributed equally to this work.


  1. Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA

    • J. Justin Milner
    • , Clara Toma
    • , Bingfei Yu
    • , Kyla Omilusik
    • , Anthony T. Phan
    • , Toan Nguyen
    •  & Ananda W. Goldrath
  2. Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California, USA

    • Kai Zhang
    •  & Wei Wang
  3. Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA

    • Dapeng Wang
    • , Adam J. Getzler
    •  & Matthew E. Pipkin
  4. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    • Shane Crotty
  5. Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA

    • Shane Crotty
  6. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA

    • Wei Wang
  7. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    • Wei Wang


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J.J.M. designed and performed experiments, analysed the data and wrote the manuscript; C.T. assisted with the RNAi screen, transfections, transductions, tissue processing, and tumour models; B.Y. performed the computational analyses and ATAC–seq experiment; K.Z. assisted with computational analyses; K.O. and T.N. assisted with tissue processing, analysis, and qPCR; A.T.P assisted with tissue processing, inducible deletion experiments, and analysis; D.W. and A.J.G. helped with the inducible deletion experiments, RNA-seq analysis, and tumour models; S.C. provided reagents and advice; W.W. supervised the computational analysis and contributed advice; M.E.P. and A.W.G. supervised the project, designed experiments, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Matthew E. Pipkin or Ananda W. Goldrath.

Reviewer Information Nature thanks F. Carbone, D. Mucida, A. Schietinger and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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