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dc.contributor.authorVanValkenburgh, Jeffrey
dc.contributor.authorAlbu, Diana I.
dc.contributor.authorBapanpally, Chandra
dc.contributor.authorCasanova, Sarah
dc.contributor.authorCalifano, Danielle
dc.contributor.authorJones, David M.
dc.contributor.authorIgnatowicz, Leszek
dc.contributor.authorKawamoto, Shimpei
dc.contributor.authorFagarasan, Sidonia
dc.contributor.authorJenkins, Nancy A.
dc.contributor.authorCopeland, Neal G.
dc.contributor.authorLiu, Pentao
dc.contributor.authorAvram, Dorina
dc.date.accessioned2012-10-26T16:29:31Z
dc.date.available2012-10-26T16:29:31Z
dc.date.issued2011-09-26en_US
dc.identifier.citationJ Exp Med. 2011 Sep 26; 208(10):2069-2081en_US
dc.identifier.issn1540-9538en_US
dc.identifier.pmid21875956en_US
dc.identifier.doi10.1084/jem.20102683en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/678
dc.description.abstractDysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-b treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-b and generation of iTreg cells.
dc.rights© 2011 VanValkenburgh et al.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshCD4-Positive T-Lymphocytesen_US
dc.subject.meshColonen_US
dc.subject.meshForkhead Transcription Factorsen_US
dc.subject.meshGene Expression Profilingen_US
dc.subject.meshGene Expression Regulationen_US
dc.subject.meshHumansen_US
dc.subject.meshInflammatory Bowel Diseasesen_US
dc.subject.meshIntegrinsen_US
dc.subject.meshInterleukin-10en_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57BLen_US
dc.subject.meshMice, Transgenicen_US
dc.subject.meshReceptors, CCRen_US
dc.subject.meshRepressor Proteinsen_US
dc.subject.meshT-Lymphocytes, Regulatoryen_US
dc.subject.meshTumor Suppressor Proteinsen_US
dc.titleCritical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel diseaseen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3182057en_US
dc.contributor.corporatenameCenter for Biotechnology and Genomic Medicine
refterms.dateFOA2019-04-10T00:31:36Z
html.description.abstractDysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-b treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-b and generation of iTreg cells.


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