Bach2 Regulates Homeostasis of Foxp3+ Regulatory T Cells and Protects against Fatal Lung Disease in Mice
Copyright policy )Bach2 Regulates Homeostasis of Foxp3+ Regulatory T Cells and Protects against Fatal Lung Disease in Mice
Abstract Variants of the Bach2 gene are linked to vitiligo, celiac disease, and type 1 diabetes, but the underlying immunological mechanisms are unknown. In this study, we demonstrate that Bach2 plays crucial roles in maintaining T cell quiescence and governing the differentiation, activation, and survival of Foxp3+ regulatory T (Treg) cells. Bach2-deficient T cells display spontaneous activation and produce elevated levels of Th1/Th2-type cytokines. Without Bach2, Treg cells exhibit diminished Foxp3 expression, depleted numbers, hyperactivation, enhanced proliferation, and profound loss of competitive fitness in vivo. Mechanistically, reduced survival of Bach2-deficient Treg cells was associated with reduced Bcl-2 and Mcl-1 levels and elevated Bim/Bcl-2 ratio. Additionally, Bach2 deficiency induced selective loss of Helios−Foxp3+ Treg cells and a Treg cell transcriptome skewed toward the Th1/Th2 effector program at the expense of the Treg program. In vitro experiments confirmed that Bach2: 1) is indispensable for TCR/TGF-β–induced Foxp3 expression; and 2) mitigates aberrant differentiation of Treg cells by repression of the competing Gata3-driven Th2 effector program. Importantly, perturbations in the differentiation of induced Treg cells was linked to a fatal Th2-type chronic inflammatory lung disease in Bach2-deficient mice. Thus, Bach2 enforces T cell quiescence, promotes the development and survival of Treg lineage, restrains aberrant differentiation of Treg cells, and protects against immune-mediated diseases.
- University of Wisconsin System United States
- University of Wisconsin–Madison United States
- University of Wisconsin–Oshkosh United States
- UW Carbone Cancer Center United States
- University of Wisconsin Hospital and Clinics United States
Mice, Knockout, Lymphopoiesis, Molecular Sequence Data, Forkhead Transcription Factors, Lymphocyte Activation, T-Lymphocytes, Regulatory, Specific Pathogen-Free Organisms, Mice, Inbred C57BL, Mice, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, Proto-Oncogene Proteins c-bcl-2, Radiation Chimera, Animals, Cytokines, Homeostasis, Myeloid Cell Leukemia Sequence 1 Protein, Positive Regulatory Domain I-Binding Factor 1, Pulmonary Eosinophilia, Cells, Cultured
Mice, Knockout, Lymphopoiesis, Molecular Sequence Data, Forkhead Transcription Factors, Lymphocyte Activation, T-Lymphocytes, Regulatory, Specific Pathogen-Free Organisms, Mice, Inbred C57BL, Mice, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, Proto-Oncogene Proteins c-bcl-2, Radiation Chimera, Animals, Cytokines, Homeostasis, Myeloid Cell Leukemia Sequence 1 Protein, Positive Regulatory Domain I-Binding Factor 1, Pulmonary Eosinophilia, Cells, Cultured
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