MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Tsui C, Kretschmer L, Rapelius S, Gabriel SS, Chisanga D, Knoepper K, Utzschneider DT, Nuessing S, Liao Y, Mason T, Torres SV, Wilcox SA, Kanev K, Jarosch S, Leube J, Nutt SL, Zehn D, Parish IA, Kastenmueller W, Shi W, Buchholz VR, Kallies A (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Nature Nature Research

Book Volume: 609

Pages Range: 354-360

Journal Issue: 7926

DOI: 10.1038/s41586-022-05105-1

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.

Involved external institutions

The University of Melbourne AU Australia (AU) Technische Universität München (TUM) DE Germany (DE) Olivia Newton-John Cancer Research Institute AU Australia (AU) Julius-Maximilians-Universität Würzburg DE Germany (DE) Peter MacCallum Cancer Centre AU Australia (AU) Walter and Eliza Hall Institute of Medical Research (WEHI) AU Australia (AU)

How to cite

APA:

Tsui, C., Kretschmer, L., Rapelius, S., Gabriel, S.S., Chisanga, D., Knoepper, K.,... Kallies, A. (2022). MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature, 609(7926), 354-360. https://dx.doi.org/10.1038/s41586-022-05105-1

MLA:

Tsui, Carlson, et al. "MYB orchestrates T cell exhaustion and response to checkpoint inhibition." Nature 609.7926 (2022): 354-360.

BibTeX: Download