Superantigen-induced CD4+ T cell tolerance is associated with DNA methylation and histone hypo-acetylation at cytokine gene loci.
Anergy is an important mechanism of peripheral tolerance in which T cells lose the capacity to produce proinflammatory cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFNgamma). To determine whether the induction of T-cell anergy in vivo is associated with epigenetic changes that oppose cytokine gene expression, we measured DNA methylation and histone acetylation at the IL2 and IFNgamma loci in CD4+ T cells from mice tolerant to a viral superantigen. Tolerant T cells exhibited more DNA methylation and less histone acetylation at the regulatory regions of the IL2 and IFNgamma genes than effector T cells, which are able to produce IL-2 and IFNgamma. These data show that T-cell anergy in this model is associated with epigenetic modifications that oppose gene expression, and suggest that these mechanisms may be important in the maintenance of tolerance.
Thomas
R M
RM
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Saouaf
S J
SJ
Wells
A D
AD
D000107:Acetylation; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D018089:Superantigens / Q000276:immunology*
D000956:Antigens, Viral; D006657:Histones; D007376:Interleukin-2; D018089:Superantigens; D007371:Interferon-gamma