Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells.
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.
Harris
John E
JE
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Bishop
Kenneth D
KD
Phillips
Nancy E
NE
Mordes
John P
JP
Greiner
Dale L
DL
Rossini
Aldo A
AA
Czech
Michael P
MP
D000818:Animals; D018106:CD28 Antigens / Q000494:pharmacology; D017252:CD3 Complex / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000276:immunology*; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051767:Early Growth Response Protein 2; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D020868:Gene Silencing; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D016335:Zinc Fingers / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D007376:Interleukin-2; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases