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

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 Knight, Sinead Reading, Kevin Thia, Lisa A. Miosge, Debbie R. Howard, Renee Gloury, Sarah S. Gabriel, Daniel T. Utzschneider, Jane Oliaro, Jonathan D. Powell, Fabio Luciani, Joseph A. Trapani, Ricky W. Johnstone, Axel Kallies, Christopher C. Goodnow () and Ian A. Parish ()
Additional contact information
Mayura V. Wagle: Australian National University
Stephin J. Vervoort: Peter MacCallum Cancer Centre
Madison J. Kelly: Peter MacCallum Cancer Centre
Willem Byl: The Kirby Institute for Infection and Immunity, UNSW
Timothy J. Peters: Garvan Institute of Medical Research
Ben P. Martin: Peter MacCallum Cancer Centre
Luciano G. Martelotto: University of Melbourne
Simone Nüssing: Peter MacCallum Cancer Centre
Kelly M. Ramsbottom: Peter MacCallum Cancer Centre
James R. Torpy: Garvan Institute of Medical Research
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
Sarah S. Gabriel: The University of Melbourne
Daniel T. Utzschneider: The University of Melbourne
Jane Oliaro: Peter MacCallum Cancer Centre
Jonathan D. Powell: Johns Hopkins University of Medicine
Fabio Luciani: The Kirby Institute for Infection and Immunity, UNSW
Joseph A. Trapani: Peter MacCallum Cancer Centre
Ricky W. Johnstone: Peter MacCallum Cancer Centre
Axel Kallies: The University of Melbourne
Christopher C. Goodnow: Australian National University
Ian A. Parish: Australian National University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23044-9

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