Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [RNA-seq II]

The differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells is strictly controlled by T cell receptor (TCR) signals; however, the molecular regulators of these processes are incompletely known. Here we found that Bach2 was a key regulator of Treg cell differentiation and homeostasis downstream of TCR signalling. Bach2 prevented premature differentiation of fully suppressive effector (e)Treg cells, limited IL-10 production and was required for the development of peripherally induced (p)Treg cells in the gastrointestinal tract. We found that Bach2 attenuated TCR signalling-induced and IRF4-dependent Treg cell differentiation programs. Deletion of IRF4 promoted inducible Treg cell differentiation and rescued pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalised eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracted DNA-binding activity of IRF4 and limited chromatin accessibility, thereby attenuating IRF4-dependent transcriptional programs. Thus, Bach2 balanced TCR signalling induced transcriptional activity of IRF4 to maintain Treg cell homeostasis. RNA-sequencing of flow cytometrically sorted splenic Treg cells from Bach2-flox/Foxp3-cre or Foxp3-cre control mice

Foxp3阳性调节性T（Treg）细胞的分化与稳态严格受T细胞受体（TCR）信号调控，但目前此类过程的分子调控机制尚未完全阐明。本研究发现，Bach2是TCR信号下游调控Treg细胞分化与稳态的关键调控因子。Bach2可抑制完全具有抑制功能的效应性调节性T（eTreg）细胞的过早分化，限制白细胞介素10（IL-10）的产生，且对胃肠道中外周诱导型调节性T（pTreg）细胞的发育至关重要。研究显示，Bach2能够减弱TCR信号诱导的、依赖于干扰素调节因子4（IRF4）的Treg细胞分化程序。敲除IRF4可促进诱导型Treg细胞的分化，并在Bach2缺失的情况下挽救pTreg细胞的分化；反之，在IRF4缺陷的Treg细胞中，Bach2的缺失可使eTreg细胞的分化恢复正常。从分子机制来看，Bach2可拮抗IRF4的DNA结合活性并限制染色质可及性，从而抑制依赖于IRF4的转录程序。综上，Bach2通过平衡TCR信号诱导的IRF4转录活性，以维持Treg细胞的稳态。本研究对来自Bach2 flox/Foxp3-cre小鼠及Foxp3-cre对照小鼠的流式分选脾脏Treg细胞开展了RNA测序（RNA-sequencing）。