Transcription factors (TFs) orchestrate cell fate and lineage development by controlling gene expression in time and space. During my PhD, I studied three of them ie T-bet, Eomes and Zeb1, and their mode of action in the development of immune subsets.
Natural killer (NK) cells are innate immune cells widely recognized as important effectors during antiviral and anti-tumor responses. T-bet and Eomes are two transcription factors from the same T-box family that are homologous with each other in terms of protein sequence and DNA binding preferences. Both factors were previously shown to regulate NK cell development, but how they worked together remained unclear. During my thesis I identified complementary roles of Eomes and T-bet in the control of gene expression during NK cell maturation ie T-bet and Eomes regulate mostly different gene sets and at different maturation stages. Analysis of genomic binding revealed a significant overlap between Eomes and T-bet. Yet, in silico analysis of DNA binding suggests that Eomes and T-bet rely on distinct co-factors to allow TF-specific activity. Moreover, T-bet or Eomes also regulate chromatin accessibility resulting in the control of NK cell development.
Natural killer T (iNKT) cells are unconventional T cells bearing an invariant T cell receptor and are distinct from conventional CD4 or CD8 single positive T cells. Previous analyses suggested a role for Zeb1 in T cell development. During my PhD, I found that Zeb1 was essential for the development of NK1.1+ T cell especially iNKT cells. The truncated form of Zeb1 in the Cellophane mutant mouse abrogated NKT cell development mainly through the deregulation of TCR signaling and survival and the repression of proliferation in T cell progenitors including DN2 and DP stages. A transcriptomic analysis on WT and Cellophane DP revealed that Zeb1 regulated the expression of multiple genes involved in cell cycle and TCR signaling, which was consistent with the phenotypes that we observed in mice. Finally, multiple lines of evidence suggest that Zeb1 acts in coordination with so-called E-proteins such as TCF1 and HEB TFs during T cell development.