Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

Jeffrey VanValkenburgh, Diana I. Albu, Chandra Bapanpally, Sarah Casanova, Danielle Califano, David M. Jones, Leszek Ignatowicz, Shimpei Kawamoto, Sidonia Fagarasan, Nancy A. Jenkins, Neal G. Copeland, Pentao Liu, Dorina Avram

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Dysregulated 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-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 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-β and generation of iTreg cells.

Original languageEnglish (US)
Pages (from-to)2069-2081
Number of pages13
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
StatePublished - Sep 26 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    VanValkenburgh, J., Albu, D. I., Bapanpally, C., Casanova, S., Califano, D., Jones, D. M., Ignatowicz, L., Kawamoto, S., Fagarasan, S., Jenkins, N. A., Copeland, N. G., Liu, P., & Avram, D. (2011). Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. Journal of Experimental Medicine, 208(10), 2069-2081. https://doi.org/10.1084/jem.20102683