title: BACH2 represses effector programs to stabilize T(reg)-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 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 (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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. roychoudhuri@mail.nih.gov
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hirahara
authors.forename: Kambiz
authors.initials: K
authors.lastname: Mousavi
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Michael
authors.initials: M
authors.lastname: Bonelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciumè
authors.forename: Hossein
authors.initials: H
authors.lastname: Zare
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.forename: Barbara
authors.initials: B
authors.lastname: Dema
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Hayato
authors.initials: H
authors.lastname: Takahashi
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.forename: George
authors.initials: G
authors.lastname: Punkosdy
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Akihiko
authors.initials: A
authors.lastname: Muto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta