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Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4+ T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.
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1 This work was supported in part by National Institutes of Health Grant RO1-AI045050 (to L.M.).
2 Address correspondence and reprint requests to Dr. Laurence Morel, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275. E-mail address: morel{at}ufl.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; pDC, plasmacytoid DC; MDC, myeloid DC; CD4+CD25+ Treg, regulatory T cell; BM, bone marrow; Teff, effector T cell.
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