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.
journal_name
Naturejournal_title
Natureauthors
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,Marincoldoi
10.1038/nature12199subject
Has Abstractpub_date
2013-06-27 00:00:00pages
506-10issue
7455eissn
0028-0836issn
1476-4687pii
nature12199journal_volume
498pub_type
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