The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080187
The Journal of Experimental Medicine, Vol. 205, No. 10, 2295-2307
The Rockefeller University Press, 0022-1007 $30.00
© Zhu et al.
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ARTICLE

 Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease

Bo Zhu1, Alistair L.J. Symonds1, Joanne E. Martin1, Dimitris Kioussis2, David C. Wraith3, Suling Li4, and Ping Wang1

1 Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, University of London, London E1 2AT, England, UK
2 Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, England, UK
3 Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol BS8 1TD, England, UK
4 Department of Biological Sciences, Brunel University, Uxbridge UB8 3PH, London, England, UK

CORRESPONDENCE Ping Wang: p.wang{at}qmul.ac.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 CD44high T cells and controls their proliferation and activation. In the absence of Egr-2, CD44high, but not CD44low T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4+CD44high 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.

Abbreviations used: APC, allophycocyanin; ChIP, chromatin immunoprecipitation; cKO, conditional KO; ds, double stranded; Egr-2, early growth response gene 2.

B. Zhu and A.L.J. Symonds contributed equally to this paper.

© 2008 Zhu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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