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Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Systemic lupus erythematosus is an autoimmune disease caused by autoantibodies, including IgG anti-DNA. New Zealand Black/New Zealand White F1 female mice, a model of spontaneous polygenic systemic lupus erythematosus, tolerized with an artificial peptide (pConsensus) based on anti-DNA IgG sequences containing MHC class I and class II T cell determinants, develop regulatory CD4+CD25+ T cells and CD8+ inhibitory T cells (CD8+ Ti), both of which suppress autoantibody production. CD8+ Ti inhibit primarily via secretion of TGF-
. In the present study, we show that the inhibitory function of CD8+ T cells from tolerized mice is sustained for up to 8 wk and at all times depends on expression of Foxp3. Both CD28-positive and CD28-negative CD8+ T cells contain inhibitory cells, but the expression of mRNA for Foxp3 and for TGF- is higher and lasts longer in the CD28– subset. In vitro addition of TGF- (in the presence of IL-2) induces Foxp3 expression in a dose-response manner. Gene inhibition or blockade with small interfering RNA of Foxp3 abrogates the ability of the CD8+ Ti to inhibit anti-DNA production and the proliferation of CD4+ Th cells. Moreover, a significant correlation between expression of Foxp3 and ability of CD8+ Ti to secrete TGF- is observed. Therefore, CD8+ Ti in this system of tolerance are similar to CD4+CD25+ regulatory T cells in their dependence on expression of Foxp3, and there may be a bidirectional Foxp3/TGF- autocrine loop that determines the ability of the CD8+ T cells to control autoimmunity.
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1 This work was supported by National Institutes of Health Grants AI 46776 (to B.H.H.) and AI63515 and AR53239 (to A.L.), awards from Skirball (to B.H.H. and A.L.), the Tina C. Foundation (to B.H.H. and R.P.S.), and gifts from the Horchow Family Foundation and Jeanne Rappaport.
2 Address correspondence and reprint requests to Dr. Bevra H. Hahn, Division of Rheumatology, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095. E-mail address: bhahn{at}mednet.ucla.edu
3 Abbreviations used in this paper: Ti, inhibitory T cell; nCD, naive CD; pCons, pConsensus; siRNA, small interfering RNA; tCD, tolerized CD; Treg, T regulatory.
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