Rapamycin Inhibits Innate and Adaptive Immune Functions of Human Plasmacytoid Dendritic Cells

Abstract

Introduction: Rapamycin is an anti-proliferative drug used to prevent organ transplant rejection and to treat cancer. Plasmacytoid dendritric cells (PDC) are important in innate immunity as they are the principal producers of IFN-α, and in adaptive immunity by presentation of antigens to T cells. PDC are critically involved in immunity to viral infections and in the pathogenesis of auto-immune disorders like Systemic Lupus Erythematosus (SLE). Here we report that innate and adaptive immune functions of human PDC are differentially regulated by Toll-Like Receptors (TLR) and CD40, and that rapamycin inhibits both innate and adaptive immune functions of PDC. Results: Human PDC activated by TLR-7 or TLR-9 ligands produced high amounts of IFN-α, but exhibited a weak T cell stimulatory capacity. Conversely, PDC activated by CD40-ligation failed to produce IFN-α, but induced robust allogeneic T cell proliferation and effector functions, among which production of pro-inflammatory cytokines IFN-gamma, TNF-alpha and IL-17. Combined stimulation via CD40 and TLR further upregulated the capacity of PDC to stimulate pro-inflammatory cytokine secretion by T cells. Rapamycin inhibited production of IFN-α by PDC, and suppressed the capacity of PDC to stimulate allogeneic T cell effector functions. Reduction of T-cell stimulatory capacity was most pronounced when rapamycin was added during activation of PDC via CD40, and was associated with inhibition of CD40 expression on PDC. Conclusions: Activation of human PDC via TLR stimulates their innate immune functions, while activation via CD40 stimulates their adaptive immune functions. Rapamycin inhibits both innate and adaptive immune functions of human PDC, and may therefore constitute a novel treatment option for SLE, but increase susceptibility to viral infections.