@article{4fb5669628654e3298dae5e6e16bacf1,
title = "Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell Insufficiency",
abstract = "Regulatory T (Treg) cells, driven by the Foxp3 transcription factor, are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in vitro function are not markedly altered in Foxp3gfp NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGF-β-induced Treg cell development was reduced. Foxp3gfp was unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.",
author = "Bettini, {Matthew L.} and Fan Pan and Maria Bettini and David Finkelstein and Rehg, {Jerold E.} and Stefan Floess and Bell, {Bryan D.} and Ziegler, {Steven F.} and Jochen Huehn and Pardoll, {Drew M.} and Vignali, {Dario A.A.}",
note = "Funding Information: We thank S. Rudensky and H. Chi for mice; M. Turnis for performing B16 injections; K. Vignali for technical assistance; M. Smeltzer for biostatistical support; K. Forbes, A. Castellaw, and A. McKenna for maintenance, breeding, and genotyping of mouse colonies; R. Cross, G. Lennon, and S. Morgan for FACS; the staff of the Shared Animal Resource Center at St. Jude for animal husbandry; the Veterinary Pathology Core Laboratory at St. Jude for histology and immunohistochemistry support; and the Hartwell Center for Biotechnology and Bioinformatics at St. Jude for real-time PCR primer/probe synthesis. DNA methylation experiments were developed and performed by U. Baron and S. Olek at Epiontis GmbH. Supported by the National Institutes of Health (AI039480, AI091977, DK089125 to D.A.A.V.), a Hartwell Postdoctoral Fellowship (to M.L.B.), JDRF Postdoctoral Fellowship (3-2009-594 to M.B.), the St. Jude National Cancer Institute Center (CA-21765 to D.A.A.V. and J.E.R.), the American Lebanese Syrian Associated Charities (to D.A.A.V. and J.E.R.), and the German Research Foundation (DFG, SFB621 and SFB738 to J.H.). ",
year = "2012",
month = may,
day = "25",
doi = "10.1016/j.immuni.2012.03.020",
language = "English (US)",
volume = "36",
pages = "717--730",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",
}