Abstract

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking.