Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Tom Sidwell,Axel Kallies,Ajithkumar Vasanthakumar,Christoph Thelemann,Christian R Engwerda,Peggy P Teh,Alexandra L Garnham,Wei Shi,Yang Liao,Renee Gloury,Gordon K Smyth,Kohei Kometani,Tomohiro Kurosaki,Lynn Corcoran,Jonas Blume,Fabian De Labastida Rivera,David Chisanga

doi:10.1038/s41467-019-14112-2

Abstract

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

Highlights

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; molecular mechanisms that govern these processes are incompletely understood
This process requires the coordinated activity of the transcription factors interferon response factor (IRF)-4 and B lymphocyte induced maturation protein (Blimp)[1], which together drive the expression of the immunosuppressive cytokine IL-107
We detected no increase in activated conventional T cells in Bach2fl/flFoxp3Cre mice compared with controls (Supplementary Fig. 1c)

Summary

Introduction

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; molecular mechanisms that govern these processes are incompletely understood. Bach[2] attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Bach[2] balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells. Treg cell development occurs predominantly in the thymus, where high affinity T cell receptor (TCR) interactions and IL-2 signals allow for the stable expression of Foxp[32,4]. Following activation through the TCR, Treg cells can further differentiate into effector (e)Treg cells, which exhibit an activated phenotype and full suppressor function[5,6] This process requires the coordinated activity of the transcription factors interferon response factor (IRF)-4 and B lymphocyte induced maturation protein (Blimp)[1], which together drive the expression of the immunosuppressive cytokine IL-107. In addition to Foxp[3], these cells express the retinoic acid-related orphan receptor (ROR)-γt

Methods

Results

Conclusion