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

Francis M Grant; Jie Yang; Rabab Nasrallah; James Clarke; Firas Sadiyah; Sarah K Whiteside; Charlotte J Imianowski; Paula Kuo; Panagiota Vardaka; Tihomir Todorov; Nordin Zandhuis; Ilinca Patrascan; David F Tough; Kohei Kometani; Robert Eil; Tomohiro Kurosaki; Klaus Okkenhaug; Rahul Roychoudhuri

doi:10.1084/jem.20190711

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.

Authors

Francis M Grant¹, Jie Yang^{1

2}, Rabab Nasrallah¹, James Clarke^{3

4}, Firas Sadiyah^{1

2}, Sarah K Whiteside^{1

2}, Charlotte J Imianowski^{1

2}, Paula Kuo^{1

2}, Panagiota Vardaka^{1

2}, Tihomir Todorov¹, Nordin Zandhuis¹, Ilinca Patrascan^{1

2}, David F Tough⁵, Kohei Kometani^{6

7}, Robert Eil⁸, Tomohiro Kurosaki^{6

7}, Klaus Okkenhaug², Rahul Roychoudhuri^{1

2}

Affiliations

¹ Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK.
² Department of Pathology, University of Cambridge, Cambridge, UK.
³ La Jolla Institute for Allergy and Immunology, La Jolla, CA.
⁴ Cancer Research UK & National Institute for Health Research Experimental Cancer Sciences Unit, University of Southampton, Southampton, UK.
⁵ Epigenetics DPU, Immunoinflammation Therapeutic Area Unit, GSK Medicines Research Centre, Stevenage, UK.
⁶ Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
⁷ Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
⁸ Oregon Health and Science University School of Medicine, Portland, OR.

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 Therapy*
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding