Multiple studies have reported high levels of IL-10 in SLE patients and in murine models of lupus. IL-10 is a regulatory cytokine mainly produced by B cells, which use this cytokine to support their proliferation, and by myeloid cells, which use IL-10 to reduce proinflammatory responses. IL-10 is also produced by a subset of CD4+ T regulatory cells. Various manipulations of IL-10 levels with repeated administrations of anti-IL-10 neutralizing antibodies, genetic ablation or injections of recombinant cytokine have shown contradictory results, which is likely to reflect the opposite effects of this cytokine on the two major effector arms of lupus pathologenesis, namely B cells and inflammation. We have investigated the role of IL-10 in a novel congenic model of lupus, B6.Sle1.Sle2.Sle3 (B6.TC), which consists of the three NZM2410-derived SLE susceptibility loci combined on a C57BL/6 background. We first investigated in this model the source of elevated IL-10 and shown that it results from a larger number of CD4+ T cells producing the cytokine, and from a greatly increased B1-a cell pool, which is the main IL-10 producing compartment. We have then used AAV-mediated skeletal muscle gene delivery to overexpress IL-10 in young B6.TC mice and follow disease marker expression up to 7 months of age. We show here that continuous overexpression of low levels of IL-10 significantly delayed antinuclear auto-antibody production and decreased clinical nephritis. B cell phenotypes were largely unaffected, while T-cell activation was significantly reduced. This highlighted the pivotal role played by T-cell activation in this model, and suggested that this pathway could be effectively targeted for therapeutic interventions. These results also reinforce the notion that IL-10 exerts multiple functions and commend caution in equating high levels of IL-10 and increased pathogenesis in systemic autoimmunity.