Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis

Nature volume 498, pages 506–510 (2013)Cite this article

Subjects

Abstract

Through their functional diversification, distinct lineages of CD4+ T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment1. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma2, Crohn’s disease3,4, coeliac disease5, vitiligo6, multiple sclerosis7 and type 1 diabetes8. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4+ T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Spontaneous lethal inflammation in Bach2 knockout animals.
Figure 2: BACH2 is required for efficient formation of Treg cells.
Figure 3: BACH2 is required for suppression of lethal inflammation in a Treg-dependent manner.
Figure 4: BACH2 represses effector programs to stabilize iTreg cell development.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Data deposits

Massively parallel RNA and ChIP sequencing data have been deposited to the Gene Expression Omnibus under the accession number GSE45975.

References

  1. Rothenberg, E. V. & Scripture-Adams, D. D. Competition and collaboration. GATA-3, PU.1, and Notch signaling in early T-cell fate determination. Semin. Immunol. 20, 236–246 (2008)

    Article  CAS  Google Scholar 

  2. Ferreira, M. A. et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378, 1006–1014 (2011)

    Article  CAS  Google Scholar 

  3. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010)

    Article  CAS  Google Scholar 

  4. Christodoulou, K. et al. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut http://dx.doi.org/10.1136/gutjnl-2011-301833 (28 April 2012)

  5. Dubois, P. C. et al. Multiple common variants for celiac disease influencing immune gene expression. Nature Genet. 42, 295–302 (2010)

    Article  CAS  Google Scholar 

  6. Jin, Y. et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nature Genet. 44, 676–680 (2012)

    Article  CAS  Google Scholar 

  7. International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011)

  8. Cooper, J. D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nature Genet. 40, 1399–1401 (2008)

    Article  CAS  Google Scholar 

  9. Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004)

    Article  CAS  ADS  Google Scholar 

  10. Ochiai, K. et al. Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. J. Biol. Chem. 281, 38226–38234 (2006)

    Article  CAS  Google Scholar 

  11. Muto, A. et al. Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J. 29, 4048–4061 (2010)

    Article  CAS  Google Scholar 

  12. Sigmundsdottir, H. & Butcher, E. C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nature Immunol. 9, 981–987 (2008)

    Article  CAS  Google Scholar 

  13. Lloyd, C. M. et al. CC chemokine receptor (CCR)3/Eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J. Exp. Med. 191, 265–274 (2000)

    Article  CAS  Google Scholar 

  14. O’Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010)

    Article  ADS  Google Scholar 

  15. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010)

    Article  CAS  Google Scholar 

  16. Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161, 72–87 (1985)

    Article  CAS  Google Scholar 

  17. Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007)

    Article  CAS  ADS  Google Scholar 

  18. Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007)

    Article  CAS  ADS  Google Scholar 

  19. Cheng, G. et al. IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatory cells. J. Immunol. 189, 1780–1791 (2012)

    Article  CAS  Google Scholar 

  20. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001)

    Article  CAS  Google Scholar 

  21. Oyake, T. et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol. 16, 6083–6095 (1996)

    Article  CAS  Google Scholar 

  22. Crotty, S., Johnston, R. J. & Schoenberger, S. P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nature Immunol. 11, 114–120 (2010)

    Article  CAS  Google Scholar 

  23. Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195, 1003–1012 (2002)

    Article  CAS  Google Scholar 

  24. Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997)

    Article  CAS  Google Scholar 

  25. Murphy, K. M. et al. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494 (2000)

    Article  CAS  Google Scholar 

  26. Watford, W. T. et al. Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii. J. Exp. Med. 205, 2803–2812 (2008)

    Article  CAS  Google Scholar 

  27. Kashiwada, M., Cassel, S. L., Colgan, J. D. & Rothman, P. B. NFIL3/E4BP4 controls type 2 T helper cell cytokine expression. EMBO J. 30, 2071–2082 (2011)

    Article  CAS  Google Scholar 

  28. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008)

    Article  CAS  ADS  Google Scholar 

  29. Xiao, X. et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nature Immunol. 13, 981–990 (2012)

    Article  CAS  Google Scholar 

  30. Oldenhove, G. et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31, 772–786 (2009)

    Article  CAS  Google Scholar 

  31. Pesu, M. et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature 455, 246–250 (2008)

    Article  CAS  ADS  Google Scholar 

  32. Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183, 2669–2674 (1996)

    Article  CAS  Google Scholar 

  33. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012)

    Article  CAS  Google Scholar 

  34. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnol. 28, 511–515 (2010)

    Article  CAS  Google Scholar 

  35. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Programs of the National Cancer Institute (NIH) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the NIH Center for Regenerative Medicine and the JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH. We thank D. N. Roychoudhuri, D. C. Macallan, G. E. Griffin, S.A. Rosenberg, M.S. Rao, Y. Ji, D. Palmer, M. Sukumar, G. Fabozzi, K. Hanada, E. Lugli, J. H. Pan and N.Van Panhuys for discussions, A. Mixon and S. Farid for cell sorting, G. McMullen for mouse handling and Y. Luo, Y. Wakabayashi, J. Zhu, G. Gutierrez-Cruz and H. W. Sun for help with sequencing and analysis.

Author information

Author notes

  1. Kiyoshi Hirahara

    Present address: Present address: Department of Advanced Allergology of the Airway, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.,

  2. Rahul Roychoudhuri, Kiyoshi Hirahara, Kambiz Mousavi, John J. O’Shea and Nicholas P. Restifo: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, 20892, Maryland, USA

    Rahul Roychoudhuri, David Clever, Christopher A. Klebanoff, Zhiya Yu, Mahadev Rao, Pawel Muranski, Joseph G. Crompton, Luca Gattinoni & Nicholas P. Restifo

  2. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland 20892, USA,

    Kiyoshi Hirahara, Michael Bonelli, Giuseppe Sciumè, Golnaz Vahedi, Hayato Takahashi, Yuka Kanno & John J. O’Shea

  3. Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA,

    Kambiz Mousavi, Hossein Zare & Vittorio Sartorelli

  4. Laboratory of Molecular Immunogenetics, NIAMS, NIH, Bethesda, Maryland 20892, USA,

    Barbara Dema & Juan Rivera

  5. Department of Transfusion Medicine, NIH, Bethesda, 20892, Maryland, USA

    Hui Liu, Davide Bedognetti, Ena Wang & Francesco M. Marincola

  6. National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, 20892, Maryland, USA

    George Punkosdy

  7. Division of Veterinary Resources, NIH, Bethesda, 20892, Maryland, USA

    Victoria Hoffmann

  8. Sidra Medical and Research Centre, Doha, Qatar

    Francesco M. Marincola

  9. Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan,

    Atsushi Nakamura, Akihiko Muto & Kazuhiko Igarashi

  10. CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan,

    Atsushi Nakamura, Akihiko Muto & Kazuhiko Igarashi

  11. NIH Center for Regenerative Medicine, NIH, Bethesda, 20892, Maryland, USA

    Nicholas P. Restifo

Authors
  1. Rahul Roychoudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiyoshi Hirahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kambiz Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Clever
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher A. Klebanoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Bonelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giuseppe Sciumè
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hossein Zare
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Golnaz Vahedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Barbara Dema
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhiya Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hayato Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mahadev Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pawel Muranski
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Joseph G. Crompton
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. George Punkosdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Davide Bedognetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ena Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Victoria Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Juan Rivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Francesco M. Marincola
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Atsushi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Vittorio Sartorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Yuka Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Luca Gattinoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Akihiko Muto
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Kazuhiko Igarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. John J. O’Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Nicholas P. Restifo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.R., K.H., J.J.O’S. and N.P.R. wrote the manuscript and designed experiments; R.R., K.H., K.M., D.C., M.B., G.S., Y.K., B.D., Z.Y., H.T. and H.L. carried out experiments; R.R., H.Z., G.V., E.W., V.S., J.J.O’S. and N.P.R. analysed experiments; V.H. performed histopathological evaluations; G.P., A.N., A.M. and K.I. contributed reagents; C.A.K., M.R., P.M., J.G.C., J.R., D.B., A.N., A.M., F.M.M., L.G., V.S. and K.I. edited the manuscript.

Corresponding authors

Correspondence to Rahul Roychoudhuri, John J. O’Shea or Nicholas P. Restifo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-25 and Supplementary Tables 1-7. (PDF 6521 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roychoudhuri, R., Hirahara, K., Mousavi, K. et al. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis. Nature 498, 506–510 (2013). https://doi.org/10.1038/nature12199

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12199

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing