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The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation

ABSTRACT: T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during infection. We find that at high concentrations T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential. Splenocyte derived CD8+ T cells from C57BL/6 mice with either a wildtype (WT) (GzmB-Cre Zeb2+/+) or GzmB-Cre Zeb2-fl/fl (Zeb2-/-) backgrounds, following 8 days post infection with LCMV-Armstrong, were subsetted into KLRG1-hi/IL-7R-lo populations (terminal effectors, TE) or KLRG1-lo/IL-7R-hi (memory precursors, MP) populations. Four experimental groups, each with 3 samples, comprised of TE+WT, MP+WT, TE+ZEB2-/-, and MP+ZEB2-/-, were profiled for gene expression utilizing a polyA RNA prep and hybridized to the Illumina microarray platform IlluminaWG-v2.0.

ORGANISM(S): Mus musculus  

SUBMITTER: Robert A Amezquita   Susan M Kaech 

PROVIDER: E-GEOD-72408 | ArrayExpress | 2015-09-15



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