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Nat Immunol. 2019 Mar;20(3):337-349. doi: 10.1038/s41590-018-0311-z. Epub 2019 Feb 18.

The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity.

Author information

1
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
2
Department of Bioinformatics, Inova Translational Medicine Institute, Fairfax, VA, USA.
3
MedImmune, Gaithersburg, MD, USA.
4
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
5
Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
6
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
7
Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.
8
Department of Microbiology, University of Virginia, Charlottesville, VA, USA.
9
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA.
10
Cellular Biomedicine Group, Gaithersburg, MD, USA.
11
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. gattinol@mail.nih.gov.

Abstract

Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.

PMID:
30778251
PMCID:
PMC6489499
[Available on 2019-08-18]
DOI:
10.1038/s41590-018-0311-z
[Indexed for MEDLINE]

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