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

J Exp Med. 2018 Apr 2;215(4):1153-1168. doi: 10.1084/jem.20171352. Epub 2018 Feb 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • Cell Lineage*
  • Cell Survival
  • Homeostasis
  • Immunity
  • Immunologic Memory
  • Lymphocytic choriomeningitis virus / physiology
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / metabolism
  • Zinc Finger E-box Binding Homeobox 2 / genetics
  • Zinc Finger E-box Binding Homeobox 2 / metabolism*
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • MicroRNAs
  • Mirn200 microRNA, mouse
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1