Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection

Kyla D. Omilusik, J. Adam Best, Bingfei Yu, Steven Goossens, Alexander Weidemann, Jessica V. Nguyen, Eve Seuntjens, Agata Stryjewska, Christiane Zweier, Rahul Roychoudhuri, Luca Gattinoni, Lynne M. Bird, Yujiro Higashi, Hisato Kondoh, Danny Huylebroeck, Jody Jonathan Haigh, Ananda W Goldrath

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59 Citations (Scopus)

Abstract

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells.
Original languageEnglish
Pages (from-to)2027 - 2039
Number of pages13
JournalJournal of Experimental Medicine
Volume212
Issue number12
DOIs
Publication statusPublished - 26 Oct 2015

Cite this

Omilusik, K. D., Best, J. A., Yu, B., Goossens, S., Weidemann, A., Nguyen, J. V., Seuntjens, E., Stryjewska, A., Zweier, C., Roychoudhuri, R., Gattinoni, L., Bird, L. M., Higashi, Y., Kondoh, H., Huylebroeck, D., Haigh, J. J., & Goldrath, A. W. (2015). Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection. Journal of Experimental Medicine, 212(12), 2027 - 2039. https://doi.org/10.1084/jem.20150194