Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease.
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.
Zhu
Bo
B
Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, University of London, London E1 2AT, England, UK.
Symonds
Alistair L J
AL
Martin
Joanne E
JE
Kioussis
Dimitris
D
Wraith
David C
DC
Li
Suling
S
Wang
Ping
P
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000033:anatomy & histology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D001323:Autoantibodies; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018960:Hyaluronan Receptors; D007376:Interleukin-2
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