Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs

Exogenous and endogenous RNA ligands of Toll-like receptor (TLR) 7 which are present during viral infection or autoimmune diseases such as systemic lupus erythematosus (SLE) directly activate DCs and B cells and thus support the generation of effector T and B lymphocytes. However, the generation of effective antiviral or autoreactive adaptive immune responses requires blocking of immunosuppression by Tregs. In this study, we show that TLR7 ligands reduce the number of Tregs generated de novo from naive murine T cells in vitro and in vivo. In the presence of TLR7-activated splenic DCs, Foxp3 was transiently induced in naive T cells by TGF-beta but was downregulated at later time points. Neutralization experiments revealed that loss of Foxp3 after initial induction was mostly dependent on IL-6 produced in the DC-T-cell cocultures containing TLR7 ligands. Thus, under the influence of TLR7 ligands fewer Tregs were generated and these expressed lower levels of Foxp3 correlating with a reduced capacity to suppress responder T-cell proliferation. Thus, we provide evidence that TLR7 ligands affect Treg-dependent immune regulation and may thereby contribute to the development of autoimmune diseases such as systemic lupus erythematosus.