MYB orchestrates T cell exhaustion and response to checkpoint inhibition
- Author(s)
- Tsui, C; Kretschmer, L; Rapelius, S; Gabriel, SS; Chisanga, D; Knöpper, K; Utzschneider, DT; Nüssing, S; Liao, Y; Mason, T; Torres, SV; Wilcox, SA; Kanev, K; Jarosch, S; Leube, J; Nutt, SL; Zehn, D; Parish, IA; Kastenmüller, W; Shi, W; Buchholz, VR; Kallies, A;
- Journal Title
- Nature
- Publication Type
- epub ahead of print
- 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 exhaustion(1,2)-is maintained by precursors of exhausted T (T(PEX)) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1(-) exhausted effector T cells(3-6). 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(+) T(PEX) cells. The transcription factor MYB is not only essential for the development of CD62L(+) T(PEX) 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(+) T(PEX) cells and depends on MYB. Our findings identify CD62L(+) T(PEX) 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.
- Publisher
- NPG
- Research Division(s)
- Advanced Technology And Biology
- PubMed ID
- 35978192
- Publisher's Version
- https://doi.org/10.1038/s41586-022-05105-1
- Open Access at Publisher's Site
https://doi.org/10.1038/s41586-022-05105-1- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-08-19 09:30:35
Last Modified: 2022-08-19 09:36:11