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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.
The transcription factor Bach2 is critical for T cell differentiation, but how it functions in Treg cells is unclear. Here the authors use a Treg-specific mouse model to show that Bach2 controls homeostasis and function of Treg cells by limiting DNA accessibility and activity of IRF4 in response to TCR signaling.
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1 The University of Melbourne, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) ; Walter and Eliza Hall Institute of Medical Research, Molecular Immunology, Melbourne, Australia (GRID:grid.1042.7)
2 Walter and Eliza Hall Institute of Medical Research, Bioinformatics Division, Melbourne, Australia (GRID:grid.1042.7) ; The University of Melbourne, Department of Medical Biology, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)
3 The University of Melbourne, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) ; Walter and Eliza Hall Institute of Medical Research, Molecular Immunology, Melbourne, Australia (GRID:grid.1042.7) ; Renal Medicine, Alfred Health, Melbourne, Australia (GRID:grid.267362.4) (ISNI:0000 0004 0432 5259) ; Western Health, Department of Nephrology, St Albans, Australia (GRID:grid.417072.7) (ISNI:0000 0004 0645 2884)
4 Walter and Eliza Hall Institute of Medical Research, Molecular Immunology, Melbourne, Australia (GRID:grid.1042.7)
5 QIMR Berghofer Medical Research Institute, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395)
6 Walter and Eliza Hall Institute of Medical Research, Molecular Immunology, Melbourne, Australia (GRID:grid.1042.7) ; The University of Melbourne, Department of Medical Biology, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)
7 RIKEN Center for Integrative Medical Sciences (IMS), Laboratory for Lymphocyte Differentiation, Kanagawa, Japan (GRID:grid.1008.9)
8 RIKEN Center for Integrative Medical Sciences (IMS), Laboratory for Lymphocyte Differentiation, Kanagawa, Japan (GRID:grid.1008.9) ; Osaka University, Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Suita, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971)
9 Walter and Eliza Hall Institute of Medical Research, Bioinformatics Division, Melbourne, Australia (GRID:grid.1042.7) ; University of Melbourne, School of Mathematics and Statistics, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)
10 Walter and Eliza Hall Institute of Medical Research, Bioinformatics Division, Melbourne, Australia (GRID:grid.1042.7) ; The University of Melbourne, School of Computing and Information Systems, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)