Bach2 attenuates T cell receptor-dependent transcription to fine-tune regulatory T cell differentiation

Abstract

Abstract The differentiation of regulatory T (Treg) cells is strictly controlled by T cell receptor (TCR) signals. However, the downstream regulators of this process are incompletely understood. Here we have found that Bach2 blocks the genomic binding of the TCR-induced transcription factor IRF4, attenuating TCR-dependent transcriptional programs to fine-tune Treg cell development and differentiation. In the absence of Bach2 we observed an increase in TCR-driven Treg cell outcomes, including the enhanced differentiation of effector Treg cells and thymic Treg precursor cells, and a reduction in peripheral Treg cell differentiation. Additional loss of the TCR-responsive transcription factor IRF4 was sufficient to normalise frequencies of each of these Treg cell populations in the absence of Bach2. Transcriptomic analysis identified significant deregulation of gene expression in Bach2-deficient cells which was dependent upon IRF4 expression. Assessing genome-wide occupancy of these transcription factors, we found Bach2 to restrict access of IRF4 to most of its genomic binding sites. Together, these data indicate that Bach2 inhibits IRF4-dependent transcription by blocking its access to their shared binding sites. Our work reveals Bach2 and IRF4 to drive opposing programs in Treg cell development and differentiation. Bach2 maintains the functional quiescence of Treg cells, in large part by blocking the genomic binding of IRF4 to attenuate the transcriptional program of TCR signalling.