title: 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.
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706;
authors.forename: Eui Ho
authors.initials: EH
authors.lastname: Kim
authors.forename: David J
authors.initials: DJ
authors.lastname: Gasper
authors.forename: Song Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Erin Hemmila
authors.initials: EH
authors.lastname: Plisch
authors.forename: John
authors.initials: J
authors.lastname: Svaren
authors.forename: M
authors.initials: M
authors.lastname: Suresh
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C513258:Prdm1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1