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

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 beta (TGF-beta) 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-beta induced and sustained Zeb1 expression in maturing memory CD8(+) T cells. Meanwhile, both TGF-beta 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.