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

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 within 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 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 upon adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8(+) T cell stemness and highlight its therapeutic potential.