Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice

J Immunol. 2014 Feb 1;192(3):985-95. doi: 10.4049/jimmunol.1302378. Epub 2013 Dec 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / physiology*
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology
  • Gene Expression Regulation / immunology
  • Homeostasis
  • Lymphocyte Activation
  • Lymphopoiesis / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Pulmonary Eosinophilia / immunology
  • Pulmonary Eosinophilia / pathology
  • Pulmonary Eosinophilia / prevention & control*
  • Radiation Chimera
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transcription, Genetic

Substances

  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1

Associated data

  • GEO/GSE52337