T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function

Abstract

Recent data illustrate a key role for the transcriptional regulator bric-a-brac, tramtrack, and broad complex and cap'n'collar homology (Bach)2 in orchestrating T cell differentiation and function. Although Bach2 has a well-described role in B cell differentiation, emerging data show that Bach2 is a prototypical member of a novel class of transcription factors that regulates transcriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data demonstrate specific roles for Bach2 in favoring regulatory T cell generation, restraining effector T cell differentiation, and potentiating memory T cell development. Evidence suggests that Bach2 regulates various facets of T cell function by repressing other key transcriptional regulators such as B lymphocyte-induced maturation protein 1. In this review, we examine our present understanding of the role of Bach2 in T cell function and highlight the growing evidence that this transcriptional repressor functions as a key regulator involved in maintenance of T cell quiescence, T cell subset differentiation, and memory T cell generation.

Figure 1. Bach2 Basics

A) Schematic representation of Bach2 protein structure. Broad complex-tamtrack-bric-a-brac (BTB) region, basic region, and leucine zipper are depicted. B) DNA binding motif for Bach2. Muscloaponeurotic fibrosarcoma (Maf), Maf-recognition element (MARE).

Figure 2. Bach2 expression in T cells and its role in CD4 T cell subset differentiation

A) Bach2 mRNA expression increases as T cells differentiate and mature into single positive T cells in the thymus. Once in the periphery, Bach2 mRNA expression declines when T cells are activated and develop into effector T cells. Expression profiles in phenotypically and functionally distinct memory T cell subsets are unknown. B) Bach2 expression promotes Treg differentiation, whereas Bach2 suppresses factors involved in Th1, Th2 and Th17 subset formation. The role of Bach2 in Tfh and Th9 development and differentiation remains to be elucidated.

Figure 3. Postulated role of Bach2 in T cell memory progression

In the absence of inflammatory cytokine signalling, antigen-activated T cells default towards memory T cell progression. Low inflammatory conditions also bias T cells towards a memory phenotype, whereas high systemic inflammatory events divert T cells towards an effector phenotype. The role of Bach2 in these processes and its modulation by inflammation-induced microRNA expression remain to be elucidated. Short-lived effector cells (SLEC), memory precursor effector cells (MPEC), and microRNA (miR).