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1: J Exp Med. 2008 Sep 29;205(10):2295-307. Epub 2008 Sep 8.
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Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease.

Zhu B, Symonds AL, Martin JE, Kioussis D, Wraith DC, Li S, Wang P.

Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, University of London, London E1 2AT, England, UK.

Maintaining tolerance of T cells to self-antigens is essential to avoid autoimmune disease. How self-reactive T cells are kept functionally inactive is, however, unknown. In this study, we show that early growth response gene 2 (Egr-2), a zinc-finger transcription factor, is expressed in CD44(high) T cells and controls their proliferation and activation. In the absence of Egr-2, CD44(high), but not CD44(low) T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4(+)CD44(high) T cells leads to the development of a late onset lupuslike autoimmune disease characterized by the accumulation of interferon (IFN)-gamma and interleukin (IL)-17-producing CD4(+) T cells, loss of tolerance to nuclear antigens, massive infiltration of T cells into multiple organs and glomerulonephritis. We found that the expression of cyclin-dependent kinase inhibitor p21cip1 was impaired in Egr-2-deficient T cells, whereas the expression of IFN-gamma and IL-17 in response to T cell receptor ligation was significantly increased, suggesting that Egr-2 activates the expression of genes involved in the negative regulation of T cell proliferation and inflammation. These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease.

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PMID: 18779345 [PubMed - indexed for MEDLINE]

PMCID: PMC2556781 [Available on 2009/03/29]