BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis

Rahul Roychoudhuri, Kiyoshi Hirahara, Kambiz Mousavi, David Clever, Christopher A. Klebanoff, Michael Bonelli, Giuseppe Sciumè, Hossein Zare, Golnaz Vahedi, Barbara Dema, Zhiya Yu, Hui Liu, Hayato Takahashi, Mahadev Rao, Pawel Muranski, Joseph G. Crompton, George Punkosdy, Davide Bedognetti, Ena Wang, Victoria HoffmannJuan Rivera, Francesco M. Marincola, Atsushi Nakamura, Vittorio Sartorelli, Yuka Kanno, Luca Gattinoni, Akihiko Muto, Kazuhiko Igarashi, John J. O'Shea, Nicholas P. Restifo

Research output: Contribution to journalArticle

180 Citations (Scopus)

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 commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. 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 (T reg) 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 TH 1, TH 2 and TH 17 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.

Original languageEnglish
Pages (from-to)506-510
Number of pages5
JournalNature
Volume498
Issue number7455
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

Homeostasis
Regulatory T-Lymphocytes
T-Lymphocytes
Cell Differentiation
Transcription Factors
Th17 Cells
Vitiligo
Immune System Diseases
Celiac Disease
Cell Lineage
Genetic Polymorphisms
Type 1 Diabetes Mellitus
Crohn Disease
Genes
Autoimmune Diseases
Multiple Sclerosis
Immunity
Asthma
Maintenance
Genome

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Roychoudhuri, R., Hirahara, K., Mousavi, K., Clever, D., Klebanoff, C. A., Bonelli, M., ... Restifo, N. P. (2013). BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis. Nature, 498(7455), 506-510. https://doi.org/10.1038/nature12199

BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis. / Roychoudhuri, Rahul; Hirahara, Kiyoshi; Mousavi, Kambiz; Clever, David; Klebanoff, Christopher A.; Bonelli, Michael; Sciumè, Giuseppe; Zare, Hossein; Vahedi, Golnaz; Dema, Barbara; Yu, Zhiya; Liu, Hui; Takahashi, Hayato; Rao, Mahadev; Muranski, Pawel; Crompton, Joseph G.; Punkosdy, George; Bedognetti, Davide; Wang, Ena; Hoffmann, Victoria; Rivera, Juan; Marincola, Francesco M.; Nakamura, Atsushi; Sartorelli, Vittorio; Kanno, Yuka; Gattinoni, Luca; Muto, Akihiko; Igarashi, Kazuhiko; O'Shea, John J.; Restifo, Nicholas P.

In: Nature, Vol. 498, No. 7455, 2013, p. 506-510.

Research output: Contribution to journalArticle

Roychoudhuri, R, Hirahara, K, Mousavi, K, Clever, D, Klebanoff, CA, Bonelli, M, Sciumè, G, Zare, H, Vahedi, G, Dema, B, Yu, Z, Liu, H, Takahashi, H, Rao, M, Muranski, P, Crompton, JG, Punkosdy, G, Bedognetti, D, Wang, E, Hoffmann, V, Rivera, J, Marincola, FM, Nakamura, A, Sartorelli, V, Kanno, Y, Gattinoni, L, Muto, A, Igarashi, K, O'Shea, JJ & Restifo, NP 2013, 'BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis', Nature, vol. 498, no. 7455, pp. 506-510. https://doi.org/10.1038/nature12199
Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M et al. BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis. Nature. 2013;498(7455):506-510. https://doi.org/10.1038/nature12199
Roychoudhuri, Rahul ; Hirahara, Kiyoshi ; Mousavi, Kambiz ; Clever, David ; Klebanoff, Christopher A. ; Bonelli, Michael ; Sciumè, Giuseppe ; Zare, Hossein ; Vahedi, Golnaz ; Dema, Barbara ; Yu, Zhiya ; Liu, Hui ; Takahashi, Hayato ; Rao, Mahadev ; Muranski, Pawel ; Crompton, Joseph G. ; Punkosdy, George ; Bedognetti, Davide ; Wang, Ena ; Hoffmann, Victoria ; Rivera, Juan ; Marincola, Francesco M. ; Nakamura, Atsushi ; Sartorelli, Vittorio ; Kanno, Yuka ; Gattinoni, Luca ; Muto, Akihiko ; Igarashi, Kazuhiko ; O'Shea, John J. ; Restifo, Nicholas P. / BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis. In: Nature. 2013 ; Vol. 498, No. 7455. pp. 506-510.
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AU - Rivera, Juan

AU - Marincola, Francesco M.

AU - Nakamura, Atsushi

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