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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 primarily by autoantibodies (including IgG anti-DNA) and immune complexes that cause tissue damage. After tolerization with an artificial peptide (pConsensus, pCons) based on murine anti-DNA IgG sequences containing MHC class I and class II T cell determinants, lupus-prone (NZB x NZW)F1 female (BWF1) mice develop regulatory CD4+CD25+ T cells and inhibitory CD8+ T cells, both of which suppress anti-DNA Ig production and immune glomerulonephritis. In the present work, we show that splenocytes from BWF1 mice treated with pCons had significant expansion of primarily CD8+ T cells. CD4+ T cells and B cells were each directly suppressed by CD8+ T cells from tolerized mice in a contact-independent manner. Both pCons-induced CD8+CD28+ and CD8+CD28– T cells suppressed production of anti-DNA in vitro. Silencing with small interfering RNA of Foxp3 abrogated the suppression mediated by both CD8+ T cell subsets. Additionally, CD8+ T cells from tolerized mice were weakly cytotoxic against syngeneic B cells from old anti-DNA-producing mice, but not from young mice. Importantly, pCons treatment had dual effects on CD8+ suppressor T cells from tolerized mice, increasing the intracellular expression of Foxp3 while decreasing the surface expression of PD1 molecules. Blocking PD1/PDL1 interactions in the CD8+ T cells from tolerized mice reduced their expression of Foxp3 and their ability to suppress CD4+CD25– proliferation. In contrast, blocking PD1/PDL1 in naive T cells increased Foxp3 expression. Our data suggest that tolerization with pCons activates different subsets of inhibitory/cytotoxic CD8+ T cells whose targets are both CD4+CD25– effector T cells and B cells.
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1 This work was supported by National Institutes of Health Grants AI46776 (to B.H.H.), AR53239 (to A.L.C.), AI 065645, and AR054034 (to R.P.S.), University of California–Los Angeles Senate Core Grant (to R.P.S. and B.H.H.), Arthritis Foundation Southern California Chapter Grant (to B.H.H. and R.P.S.), and gifts from the Maltz Laboratory, the Horchow family, and Jeanne Rappaport.
2 Address correspondence and reprint requests to Dr. Ram P. Singh, Division of Rheumatology, David Geffen School of Medicine, University of California, Room 32-59, 1000 Veteran Avenue, Los Angeles, CA 90095. E-mail address: rpsingh{at}mednet.ucla.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; 7AAD, 7-aminoactinomycin D; FasL, Fas ligand; FSC, forward scattering cells; MFI, mean fluorescence intensity; pCons, pConsensus; pNeg, negative control peptide; siRNA, small interfering RNA; Ti, inhibitory T; Treg, regulatory T.
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  E. V. Lourenco, C. Procaccini, F. Ferrera, N. Iikuni, R. P. Singh, G. Filaci, G. Matarese, F.-D. Shi, E. Brahn, B. H. Hahn, et al. Modulation of p38 MAPK Activity in Regulatory T Cells after Tolerance with Anti-DNA Ig Peptide in (NZB x NZW)F1 Lupus Mice J. Immunol., June 15, 2009; 182(12): 7415 - 7421. [Abstract] [Full Text] [PDF]
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