MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Tsui, C; Kretschmer, L; Rapelius, S; Gabriel, SS; Chisanga, D; Knopper, K; Utzschneider, DT; Nussing, S; Liao, Y; Mason, T; Valle Torres, S; Wilcox, SA; Kanev, K; Jarosch, S; Leube, J; Nutt, SL; Zehn, D; Parish, IA; Kastenmuller, W; Shi, W; Buchholz, VR; Kallies, A

Author(s): Tsui, C; Kretschmer, L; Rapelius, S; Gabriel, SS; Chisanga, D; Knopper, K; Utzschneider, DT; Nussing, S; Liao, Y; Mason, T; Valle Torres, S; Wilcox, SA; Kanev, K; Jarosch, S; Leube, J; Nutt, SL; Zehn, D; Parish, IA; Kastenmuller, W; Shi, W; Buchholz, VR; Kallies, A;
Details: Publication Year 2022-09-08,Volume 609,Issue #7926,Page 354-360
Journal Title: Nature
Publication Type: Research article
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.
Keywords: *CD8-Positive T-Lymphocytes/cytology/immunology; Cell Proliferation; Cell Self Renewal; Hepatocyte Nuclear Factor 1-alpha/metabolism; Immunotherapy; L-Selectin/metabolism; Precursor Cells, T-Lymphoid/cytology/immunology; *Programmed Cell Death 1 Receptor/immunology/metabolism; *Proto-Oncogene Proteins c-myb/metabolism; Viruses/immunology
Department(s): Laboratory Research
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.

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