Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells
Harris, John E. ; Bishop, Kenneth D. ; Phillips, Nancy E. ; Mordes, John P. ; Greiner, Dale L. ; Rossini, Aldo A. ; Czech, Michael P.
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Keywords
Antigens, CD28
Antigens, CD3
CD4-Positive T-Lymphocytes
Cell Line
Cell Proliferation
Clonal Anergy
Clone Cells
DNA-Binding Proteins
inhibitors
Early Growth Response Protein 2
Extracellular Signal-Regulated MAP Kinases
Gene Expression Regulation
Gene Silencing
Interleukin-2
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Phosphorylation
RNA, Small Interfering
Receptors, Antigen, T-Cell
Transcription Factors
inhibitors
Up-Regulation
Zinc Fingers
Life Sciences
Medicine and Health Sciences
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Abstract
Ag-specific immune tolerance results from the induction of cellular mechanisms that limit T cell responses to selective Ags. One of these mechanisms is characterized by attenuated proliferation and decreased IL-2 production in fully stimulated CD4(+) Th cells and is denoted T cell anergy. We report the identification of the early growth response gene (Egr-2; Krox-20), a zinc-finger transcription factor, as a key protein required for induction of anergy in cultured T cells. Gene array screening revealed high Egr-2 expression distinctly persists in anergized but not proliferating murine A.E7 T cells. In contrast, Egr-1, a related family member induced upon costimulation, displays little or no expression in the anergic state. IL-2-mediated abrogation of anergy causes rapid depletion of Egr-2 protein. Full stimulation of anergic A.E7 T cells fails to enhance IL-2 and Egr-1 expression, whereas Egr-2 expression is greatly increased. Silencing Egr-2 gene expression by small interfering RNA treatment of cultured A.E7 T cells before incubation with anti-CD3 alone prevents full induction of anergy. However, small interfering RNA-mediated depletion of Egr-2 5 days after anergy induction does not appear to abrogate hyporesponsiveness to stimulation. These data indicate that sustained Egr-2 expression is necessary to induce a full anergic state through the actions of genes regulated by this transcription factor.
Source
J Immunol. 2004 Dec 15;173(12):7331-8.