CD8+ T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression.

Systemic lupus erythematosus is an autoimmune disease caused by autoantibodies, including IgG anti-DNA. New Zealand Black/New Zealand White F 1 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-β. 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-β is higher and lasts longer in the CD28 − subset. In vitro addition of TGF-β (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-β 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-β autocrine loop that determines the ability of the CD8 + T cells to control autoimmunity.