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BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis

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.

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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.

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. 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)

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 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)

    CAS  Article  Google Scholar 

  4. 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. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 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. 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)

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  ADS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 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)

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 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)

    CAS  Article  Google Scholar 

  14. 14

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

    ADS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 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)

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  ADS  Article  Google Scholar 

  18. 18

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

    CAS  ADS  Article  Google Scholar 

  19. 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)

    CAS  Article  Google Scholar 

  20. 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)

    CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. 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)

    CAS  Article  Google Scholar 

  23. 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)

    CAS  Article  Google Scholar 

  24. 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)

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 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)

    CAS  Article  Google Scholar 

  27. 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)

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  ADS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 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)

    CAS  Article  Google Scholar 

  31. 31

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

    CAS  ADS  Article  Google Scholar 

  32. 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)

    CAS  Article  Google Scholar 

  33. 33

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

    CAS  Article  Google Scholar 

  34. 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)

    CAS  Article  Google Scholar 

  35. 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.

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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.

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

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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

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