Understanding transcriptional regulation of terminal T cell differentiation: a focus on Blimp1

Abstract

The transcription factor Blimp1 is a critical regulator of the terminal differentiation of effector CD8+ T cells during acute viral infections. Blimp1-deficient CD8+ T cells failed to develop into short-lived effector cells. Blimp1 is also indispensable for the differentiation of activated Treg cells and is required for IL-10 production by Treg cells. However, it was not known what genes were regulated by Blimp1 in those two populations and how they were regulated. Here I present data showing that Blimp1 globally regulates genes involved in migration, effector function and transcription in T cells that promote the cell fate associated with terminal differentiation. Although Blimp1 is required for the downregulation of transcriptional signatures associated with naïve and memory T cells including Tcf7 and Id3, its expression is equally crucial for gene upregulation in vivo, such as Gzmb in CD8+ T cells and Il10 in Treg cells. Using Il10 as a model gene, I show data supporting the role of Blimp1 together with IRF4 in mediating open chromatin for Il10 transcription.

Numerous cytokines have been shown to upregulation Blimp1 expression in vitro but their in vivo roles and effects on Blimp1 were not addressed. In particular, IL-2 has been described as an important inducer of Blimp1 in vitro and IL-2 signalling is essential for CTL differentiation. I show here that IL-2 is not mandatory for Blimp1 expression in vitro or in vivo, and Blimp1 could be redundantly upregulated by the pro-inflammatory cytokine IL-12. However, IL-2 is required in an environment where inflammation is limited and induces both Blimp1 and T-bet in effector CTLs. T-bet and Blimp1 function independently in parallel transcriptional pathways that mediate similar aspects of effector CTL differentiation.