ZEB2 plays a role in promoting T-bet expression and terminal differentiation of CD8+ T cells (121.10)

Abstract

Abstract We are interested in deciphering the transcriptional programs that underlie the differentiation of the effector CD8 T cell response. Prior work has shown T-bet operates in a gradient fashion, with higher T-bet expression being critical for the development of terminal effector (TE) CD8 T cells. Expression profiling revealed that T-bet regulates ZEB2, a transcriptional repressor that is expressed 10 fold higher in TE cells compared to memory precursor (MP) effector CD8 T cells. To further investigate what role ZEB2 might play in promoting terminal differentiation of CD8 T cells we conditionally knocked out ZEB2 in activated CD8 T cells using Granzyme B Cre ZEB2 flox/flox mice (ZEB2 KO). Upon infection with LCMV, the CD8 T cell expansion in the ZEB2 KO was about half that of wild type mice. The ZEB2 KO CD8 T cells showed an accelerated maturation of the effector CD8 T cell compartment to a memory phenotype with increased IL-2 production and the acquisition of CD62L. Further analysis revealed that these phenotypes might be largely due to the reduction of the TE subset. In the absence of ZEB2, TE CD8 T cells adopt some MP characteristics such as CD27, CXCR3, and Eomes but reduced T-bet and Blimp-1. Our observations suggest that ZEB2 is critical for the maintenance of the transcriptional program that drives terminal differentiation including T-bet. Hence, we propose that ZEB2 and T-bet operate in a positive-feedback mechanism to drive CD8 T cells towards terminal differentiation.