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 language | English (US) |
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Pages (from-to) | 1153-1168 |
Number of pages | 16 |
Journal | Journal of Experimental Medicine |
Volume | 215 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2018 |
Funding
We thank the members of the Kaech, Craft, Flavell, and Lu laboratories for helpful comments and scientific advice in generation of Zeb1f/f mice, in particular X. Jiang, J. Stein, C. Hughes, and L. Borelli for technical support. We also thank H. Hasuwa for providing miR-200b/a/429 KO mice, M. Bevan for providing Tgfbr2f/f LckCre mice, and J. Cheng for the miR-200 overexpression constructs. This work was supported by the National Institutes of Health (grants R01AI07469905, R01AI07469905S, and R37AI066232 to S.M. Kaech), National Institute of Allergy and Infectious Diseases (National Research Service Award, Ruth Kirschstein Predoctoral Fellowship F31AI084500-01 to C.X. Dominguez), Howard Hughes Medical Institute (to R.A. Amezquita and T. Guan), and Chinese Scholarship Council/Yale World Scholars Fellowship (to T. Guan)
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology