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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance

Author

Listed:
  • Mayura V. Wagle

    (Australian National University)

  • Stephin J. Vervoort

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Madison J. Kelly

    (Peter MacCallum Cancer Centre)

  • Willem Byl

    (The Kirby Institute for Infection and Immunity, UNSW
    University of New South Wales)

  • Timothy J. Peters

    (Garvan Institute of Medical Research
    University of New South Wales)

  • Ben P. Martin

    (Peter MacCallum Cancer Centre)

  • Luciano G. Martelotto

    (University of Melbourne)

  • Simone Nüssing

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Kelly M. Ramsbottom

    (Peter MacCallum Cancer Centre)

  • James R. Torpy

    (Garvan Institute of Medical Research
    University of New South Wales)

  • Deborah Knight

    (Peter MacCallum Cancer Centre)

  • Sinead Reading

    (Peter MacCallum Cancer Centre)

  • Kevin Thia

    (Peter MacCallum Cancer Centre)

  • Lisa A. Miosge

    (Australian National University)

  • Debbie R. Howard

    (Australian National University)

  • Renee Gloury

    (The University of Melbourne
    The University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Sarah S. Gabriel

    (The University of Melbourne
    The University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Daniel T. Utzschneider

    (The University of Melbourne
    The University of Melbourne)

  • Jane Oliaro

    (Peter MacCallum Cancer Centre
    University of Melbourne
    Monash University)

  • Jonathan D. Powell

    (Johns Hopkins University of Medicine)

  • Fabio Luciani

    (The Kirby Institute for Infection and Immunity, UNSW
    University of New South Wales)

  • Joseph A. Trapani

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Ricky W. Johnstone

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Axel Kallies

    (The University of Melbourne
    The University of Melbourne)

  • Christopher C. Goodnow

    (Australian National University
    University of New South Wales
    Garvan Institute of Medical Research)

  • Ian A. Parish

    (Australian National University
    Peter MacCallum Cancer Centre
    University of Melbourne)

Abstract

Chronic stimulation of CD8+ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.

Suggested Citation

  • Mayura V. Wagle & Stephin J. Vervoort & Madison J. Kelly & Willem Byl & Timothy J. Peters & Ben P. Martin & Luciano G. Martelotto & Simone Nüssing & Kelly M. Ramsbottom & James R. Torpy & Deborah Kni, 2021. "Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23044-9
    DOI: 10.1038/s41467-021-23044-9
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