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The Journal of Immunology, 2004, 173: 7331-7338.
Copyright © 2004 by The American Association of Immunologists

Early Growth Response Gene-2, a Zinc-Finger Transcription Factor, Is Required for Full Induction of Clonal Anergy in CD4+ T Cells1

John E. Harris2,*, Kenneth D. Bishop2,*, Nancy E. Phillips{dagger}, John P. Mordes{dagger}, Dale L. Greiner{dagger},{ddagger}, Aldo A. Rossini*,{dagger},{ddagger} and Michael P. Czech3,*

* Program in Molecular Medicine, {dagger} Department of Medicine, and {ddagger} Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655

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.


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