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

Gautam S, Fioravanti J, Zhu W, Le Gall JB, Brohawn P, Lacey NE, Hu J, Hocker JD, Hawk NV, Kapoor V, Telford WG, Gurusamy D, Yu Z, Bhandoola A, Xue HH, Roychoudhuri R, Higgs BW, Restifo NP, Bender TP, Ji Y, Gattinoni L (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Nature Immunology Nature Research

Book Volume: 20

Pages Range: 337-349

Journal Issue: 3

DOI: 10.1038/s41590-018-0311-z

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.

Involved external institutions

National Cancer Institute (NCI) US United States (USA) (US) Inova Translational Medicine Institute (ITMI) US United States (USA) (US) AstraZeneca UK Limited GB United Kingdom (GB) University of Iowa US United States (USA) (US) Babraham Institute GB United Kingdom (GB) University of Virginia (UVA) US United States (USA) (US)

How to cite

APA:

Gautam, S., Fioravanti, J., Zhu, W., Le Gall, J.B., Brohawn, P., Lacey, N.E.,... Gattinoni, L. (2019). The transcription factor c-Myb regulates CD8+T cell stemness and antitumor immunity. Nature Immunology, 20(3), 337-349. https://doi.org/10.1038/s41590-018-0311-z

MLA:

Gautam, Sanjivan, et al. "The transcription factor c-Myb regulates CD8+T cell stemness and antitumor immunity." Nature Immunology 20.3 (2019): 337-349.

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