MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
Nature, 2022/09;609(7926):354-360.
Tsui C[1], Kretschmer L[2], Rapelius S[2], Gabriel SS[1], Chisanga D[3, 4, 5, 6], Knöpper K[7], Utzschneider DT[1], Nüssing S[8, 9], Liao Y[3, 4, 5, 6], Mason T[1], Torres SV[1], Wilcox SA[4], Kanev K[10], Jarosch S[2], Leube J[2], Nutt SL[4], Zehn D[10], Parish IA[8, 9], Kastenmüller W[7], Shi W[3, 4, 5, 11], Buchholz VR[12], Kallies A[13]
Affiliations
PMID: 35978192DOI: 10.1038/s41586-022-05105-1
Impact factor: 69.504
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.
MeSH terms
CD8-Positive T-Lymphocytes; Cell Proliferation; Cell Self Renewal; Hepatocyte Nuclear Factor 1-alpha; Immunotherapy; L-Selectin; Precursor Cells, T-Lymphoid; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins c-myb; Viruses
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