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

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 mAbcoated 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-TCRβ mAb in the presence of syngeneic BMDCs, and T_reg cells from gardiquimodtreated mice exhibited enhanced in vitro suppressor function. Moreover, levels of T _resp cell-secreted IL-2 and IFN-γ 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.