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BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis


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


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.


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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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Authors and Affiliations



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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The authors declare no competing financial interests.

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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).

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