ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates

Tianxia Guan, Claudia X. Dominguez, Robert A. Amezquita, Brian J. Laidlaw, Jijun Cheng, Jorge Henao-Mejia, Adam Williams, Richard A. Flavell, Jun Lu, Susan M. Kaech

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Long-term immunity depends partly on the establishment of memory CD8+ T cells. We identified a counterregulatory network between the homologous transcription factors ZEB1 and ZEB2 and the miR-200 microRNA family, which modulates effector CD8+ T cell fates. Unexpectedly, Zeb1 and Zeb2 had reciprocal expression patterns and were functionally uncoupled in CD8+ T cells. ZEB2 promoted terminal differentiation, whereas ZEB1 was critical for memory T cell survival and function. Interestingly, the transforming growth factor β (TGF-β) and miR-200 family members, which counterregulate the coordinated expression of Zeb1 and Zeb2 during the epithelial-to-mesenchymal transition, inversely regulated Zeb1 and Zeb2 expression in CD8+ T cells. TGF-β induced and sustained Zeb1 expression in maturing memory CD8+ T cells. Meanwhile, both TGF-β and miR-200 family members selectively inhibited Zeb2. Additionally, the miR-200 family was necessary for optimal memory CD8+ T cell formation. These data outline a previously unknown genetic pathway in CD8+ T cells that controls effector and memory cell fate decisions.

Original languageEnglish
Pages (from-to)1153-1168
Number of pages16
JournalJournal of Experimental Medicine
Volume215
Issue number4
DOIs
StatePublished - Apr 1 2018

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