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 Foxp3(gfp) 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 Foxp3(gfp) NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGF-β-induced Treg cell development was reduced. Foxp3(gfp) 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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylation
-
Animals
-
Autoimmunity / genetics
-
Autoimmunity / immunology
-
Carrier Proteins / genetics
-
Carrier Proteins / immunology
-
Carrier Proteins / metabolism
-
DNA-Binding Proteins
-
Diabetes Mellitus, Type 1 / genetics
-
Diabetes Mellitus, Type 1 / immunology
-
Diabetes Mellitus, Type 1 / metabolism
-
Epigenesis, Genetic
-
Forkhead Transcription Factors / genetics
-
Forkhead Transcription Factors / immunology*
-
Forkhead Transcription Factors / metabolism*
-
Histone Acetyltransferases / genetics
-
Histone Acetyltransferases / immunology
-
Histone Acetyltransferases / metabolism
-
Histone Deacetylases / genetics
-
Histone Deacetylases / immunology
-
Histone Deacetylases / metabolism
-
Interleukin-2 / genetics
-
Interleukin-2 / immunology
-
Interleukin-2 / metabolism
-
Lysine Acetyltransferase 5
-
Mice
-
Mice, Inbred C57BL
-
Mice, Inbred NOD
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / immunology
-
Nerve Tissue Proteins / metabolism
-
Promoter Regions, Genetic
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / metabolism
-
Trans-Activators / genetics
-
Trans-Activators / immunology
-
Trans-Activators / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / immunology*
-
Transcription Factors / metabolism*
-
Transforming Growth Factor beta / genetics
-
Transforming Growth Factor beta / immunology
-
Transforming Growth Factor beta / metabolism
Substances
-
Carrier Proteins
-
DNA-Binding Proteins
-
Forkhead Transcription Factors
-
Foxp3 protein, mouse
-
Interleukin-2
-
Nerve Tissue Proteins
-
Trans-Activators
-
Transcription Factors
-
Transforming Growth Factor beta
-
Zfpn1a4 protein, mouse
-
Histone Acetyltransferases
-
Kat5 protein, mouse
-
Lysine Acetyltransferase 5
-
Hdac7 protein, mouse
-
Histone Deacetylases