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    Publication Date: 2013-06-04
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roychoudhuri, Rahul -- Hirahara, Kiyoshi -- Mousavi, Kambiz -- Clever, David -- Klebanoff, Christopher A -- Bonelli, Michael -- Sciume, 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 -- Z01 BC011037-01/Intramural NIH HHS/ -- Z99 CA999999/Intramural NIH HHS/ -- ZIA BC011037-02/Intramural NIH HHS/ -- England -- Nature. 2013 Jun 27;498(7455):506-10. doi: 10.1038/nature12199. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. roychoudhuri@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728300" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/immunology ; Basic-Leucine Zipper Transcription Factors/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology/metabolism ; Cell Differentiation/genetics/immunology ; Female ; Forkhead Transcription Factors/genetics/metabolism ; Homeostasis/genetics/*immunology ; Humans ; Immune Tolerance/genetics/immunology ; Inflammation/genetics/immunology/mortality/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes, Regulatory/cytology/drug effects/*immunology/metabolism ; Transforming Growth Factor beta/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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