Signaling through TLR7 enhances the immunosuppressive activity of murine CD4+CD25+ T regulatory cells

Abstract

Although signaling through certain TLRs is known to modulate the function of T lymphocytes, the effect of TLR7 stimulation on CD4(+)CD25(+) T(reg) cell activity has not yet been elucidated. In this study, we show that mouse CD4(+)CD25(+) T(reg) cells express TLR7 mRNA and protein. We therefore used the TLR7 agonists imiquimod, gardiquimod, and single-stranded poly(U) to show that TLR7 stimulation enhanced the ability of murine T(reg) cells to suppress anti-CD3/anti-CD28 mAb-coated bead-stimulated proliferation of syngeneic CD4(+)CD25(-) T(resp) cells. In contrast, imiquimod failed to enhance the suppressor function of T(reg) cells from mice deficient in the MyD88 adaptor protein involved in TLR7 and other TLR signal transduction. Imiquimod increased murine T(reg) cell-mediated suppression of T(resp) cell proliferation induced by anti-TCRbeta mAb in the presence of syngeneic BMDCs, and T(reg) cells from gardiquimod-treated mice exhibited enhanced in vitro suppressor function. Moreover, levels of T(resp) cell-secreted IL-2 and IFN-gamma were reduced further in the presence of T(reg) cells plus imiquimod in comparison with T(reg) cells alone. In addition, imiquimod treatment increased CD25 expression by T(reg) cells and caused exogenous IL-2 to enhance T(reg) cell suppressor function. Furthermore, combined treatment with imiquimod and IL-2 increased Foxp3 expression by T(reg) cells. Collectively, these findings suggest that TLR7 signaling enhanced the suppressor function of T(reg) cells by sensitizing T(reg) cells to IL-2-induced activation. We speculate that TLR7-stimulated enhancement of T(reg) cell suppressor function may modulate host T cell responses against ssRNA viruses.