MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Carlson Tsui, Lornez 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 & Axel Kallies (17 Aug 2022) MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature. https://doi.org/10.1038/s41586-022-05105-1

Abstract cited directly from the article:

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—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 cells. 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.

From the TUM press release:

"A research team has discovered a new subset of immune cells that play a significant role in the immune response to chronic infections and cancer. This T-cell population is also critical for immunotherapies that use checkpoint inhibitors. The discovery may provide an explanation for why immunotherapy is ineffective in some people and lead to the development of more effective therapies for cancers and severe viral infections." 

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