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 autoinumme 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-P. 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-P is higher and lasts longer in the CD28(-) subset. In vitro addition of TGF-P (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-P 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-beta autocrine loop that determines the ability of the CD8(+) T cells to control autoimmunity.