title: Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease.
abstract: Dysregulated CD4(+) T cell responses and alterations in T regulatory cells (T(reg) 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 T(reg) cells causes IBD because of proinflammatory cytokine-producing CD4(+) T cells infiltrating the colon. Provision of WT T(reg) cells prevented IBD, demonstrating that alterations in T(reg) cells are responsible for the disease. Furthermore, Bcl11b-deficient T(reg) 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 T(reg) cells (iT(reg) cells) after Tgf-β 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 T(reg) 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-β and generation of iT(reg) cells.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vanvalkenburgh
authors.forename: Diana I
authors.initials: DI
authors.lastname: Albu
authors.forename: Chandra
authors.initials: C
authors.lastname: Bapanpally
authors.forename: Sarah
authors.initials: S
authors.lastname: Casanova
authors.forename: Danielle
authors.initials: D
authors.lastname: Califano
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.forename: Leszek
authors.initials: L
authors.lastname: Ignatowicz
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kawamoto
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016023:Integrins / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054388:Receptors, CCR / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C511143:Bcl11b protein, mouse; C119309:CC chemokine receptor 9; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016023:Integrins; D054388:Receptors, CCR; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C071777:integrin alpha4beta7; D016753:Interleukin-10