MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
Nature
; 609(7926): 354-360, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-35978192
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T CD8-Positivos
/
Proteínas Proto-Oncogênicas c-myb
/
Receptor de Morte Celular Programada 1
Idioma:
En
Revista:
Nature
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Austrália