BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression

J Exp Med. 2020 Sep 7;217(9):e20190711. doi: 10.1084/jem.20190711.

Abstract

Regulatory T (Treg) cell populations are composed of functionally quiescent resting Treg (rTreg) cells which differentiate into activated Treg (aTreg) cells upon antigen stimulation. How rTreg cells remain quiescent despite chronic exposure to cognate self- and foreign antigens is unclear. The transcription factor BACH2 is critical for early Treg lineage specification, but its function following lineage commitment is unresolved. Here, we show that BACH2 is repurposed following Treg lineage commitment and promotes the quiescence and long-term maintenance of rTreg cells. Bach2 is highly expressed in rTreg cells but is down-regulated in aTreg cells and during inflammation. In rTreg cells, BACH2 binds to enhancers of genes involved in aTreg differentiation and represses their TCR-driven induction by competing with AP-1 factors for DNA binding. This function promotes rTreg cell quiescence and long-term maintenance and is required for immune homeostasis and durable immunosuppression in cancer. Thus, BACH2 supports a "division of labor" between quiescent rTreg cells and their activated progeny in Treg maintenance and function, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Cycle*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Cell Lineage
  • Cytokines / metabolism
  • Down-Regulation
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Homeostasis*
  • Humans
  • Immunosuppression*
  • Inflammation / pathology
  • Integrases / metabolism
  • Mice, Inbred C57BL
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Phenotype
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription Factor AP-1 / metabolism

Substances

  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • Transcription Factor AP-1
  • Cre recombinase
  • Integrases