Enhanced IL-6 Production by Bone Marrow Derived Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Mediated Suppression.

The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus due to the co-expression of the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of anti-nuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (T_reg), and that Sle3 results in intrinsic defects in myeloid cells that hyperactivate T cells. Here, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone-marrow derived DCs, plasmacytoid and myeloid DCs express a significantly lower level of CD80, CD86 and class II MHC than B6 controls. 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 T_reg. B6.TC DCs over-produce IL-6, which is necessary for the blockade of T_reg activity, as shown by anti-IL-6 neutralizing antibody in the suppression assays. The over-production of IL-6 by DCs and the blockade of T_reg activity maps to Sle1, which therefore not only confers a reduced number of T_reg, 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 both in number and function, and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.