Imiquimod triggers TLR7-independent apoptosis but TLR7-dependent activation in murine CD4⁺ T cells

Toll-like receptor 7 (TLR7) agonists are widely used as immunomodulatory agents, yet their direct effects on T cells remain incompletely understood. Here, we investigated the effects of imiquimod (IMQ) on purified murine CD4⁺ T cells using TLR7-deficient mice and pharmacological approaches. IMQ elicited both activating and suppressive responses in CD4⁺ T cells. Low concentrations modestly enhanced cell expansion, whereas higher concentrations reduced cell expansion and induced apoptosis in a dose-dependent manner. The suppressive and pro-apoptotic effects were preserved in TLR7-deficient CD4⁺ T cells, indicating that these effects are TLR7-independent. In contrast, IMQ-induced upregulation of the early activation marker CD69 was completely abolished in TLR7-deficient CD4⁺ T cells, demonstrating strict TLR7 dependence. We further found that thymidine and thymidine-containing oligodeoxynucleotides attenuated IMQ-induced suppression of CD4⁺ T cell expansion and apoptosis, while having little effect on CD69 induction. These findings demonstrate that IMQ elicits separable TLR7-dependent and TLR7-independent responses in murine CD4⁺ T cells and show that thymidine selectively attenuates the TLR7-independent suppressive and apoptotic effects of IMQ.