MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Carlson Tsui, Lorenz Kretschmer, Svenja Rapelius, Sarah S. Gabriel, David Chisanga, Konrad Knöpper, Daniel T. Utzschneider, Simone Nüssing, Yang Liao, Teisha Mason, Santiago Valle Torres, Stephen A. Wilcox, Krystian Kanev, Sebastian Jarosch, Justin Leube, Stephen L. Nutt, Dietmar Zehn, Ian A. Parish, Wolfgang Kastenmüller, Wei Shi, Veit R. Buchholz () and Axel Kallies ()
Additional contact information
Carlson Tsui: University of Melbourne
Lorenz Kretschmer: Technical University of Munich (TUM)
Svenja Rapelius: Technical University of Munich (TUM)
Sarah S. Gabriel: University of Melbourne
David Chisanga: Olivia Newton-John Cancer Research Institute
Konrad Knöpper: Julius-Maximilians-Universität Würzburg
Daniel T. Utzschneider: University of Melbourne
Simone Nüssing: Peter MacCallum Cancer Centre
Yang Liao: Olivia Newton-John Cancer Research Institute
Teisha Mason: University of Melbourne
Santiago Valle Torres: University of Melbourne
Stephen A. Wilcox: The Walter and Eliza Hall Institute of Medical Research
Krystian Kanev: Technical University of Munich (TUM)
Sebastian Jarosch: Technical University of Munich (TUM)
Justin Leube: Technical University of Munich (TUM)
Stephen L. Nutt: The Walter and Eliza Hall Institute of Medical Research
Dietmar Zehn: Technical University of Munich (TUM)
Ian A. Parish: Peter MacCallum Cancer Centre
Wolfgang Kastenmüller: Julius-Maximilians-Universität Würzburg
Wei Shi: Olivia Newton-John Cancer Research Institute
Veit R. Buchholz: Technical University of Munich (TUM)
Axel Kallies: University of Melbourne

Nature, 2022, vol. 609, issue 7926, 354-360

Abstract: Abstract CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion1,2—is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1− exhausted effector T cells3–6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

Date: 2022
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DOI: 10.1038/s41586-022-05105-1

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