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

Tom Sidwell, Yang Liao, Alexandra L. Garnham, Ajithkumar Vasanthakumar, Renee Gloury, Jonas Blume, Peggy P. Teh, David Chisanga, Christoph Thelemann, Fabian Labastida Rivera, Christian R. Engwerda, Lynn Corcoran, Kohei Kometani, Tomohiro Kurosaki, Gordon K. Smyth, Wei Shi and Axel Kallies ()
Additional contact information
Tom Sidwell: The University of Melbourne
Yang Liao: Walter and Eliza Hall Institute of Medical Research
Alexandra L. Garnham: Walter and Eliza Hall Institute of Medical Research
Ajithkumar Vasanthakumar: The University of Melbourne
Renee Gloury: The University of Melbourne
Jonas Blume: The University of Melbourne
Peggy P. Teh: The University of Melbourne
David Chisanga: Walter and Eliza Hall Institute of Medical Research
Christoph Thelemann: Walter and Eliza Hall Institute of Medical Research
Fabian Labastida Rivera: QIMR Berghofer Medical Research Institute
Christian R. Engwerda: QIMR Berghofer Medical Research Institute
Lynn Corcoran: Walter and Eliza Hall Institute of Medical Research
Kohei Kometani: RIKEN Center for Integrative Medical Sciences (IMS)
Tomohiro Kurosaki: RIKEN Center for Integrative Medical Sciences (IMS)
Gordon K. Smyth: Walter and Eliza Hall Institute of Medical Research
Wei Shi: Walter and Eliza Hall Institute of Medical Research
Axel Kallies: The University of Melbourne

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14112-2

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