Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

Summary Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)‐α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti‐cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll‐like receptor (TLR)‐7‐induced IFN‐α secretion potently (−64%) but TLR‐9‐induced IFN‐α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR‐7‐activated and TLR‐9‐activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR‐7‐activated and TLR‐9‐activated PDC to stimulate production of IFN‐γ and interleukin (IL)‐10 by allogeneic T cells. Surprisingly, mTOR‐inhibition enhanced the capacity of TLR‐7‐activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin‐induced up‐regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR‐7‐activated PDC enhanced their capacity to induce CD4+forkhead box protein 3 (FoxP3)+ regulatory T cells, but did not affect the generation of suppressive CD8+CD38+lymphocyte activation gene (LAG)‐3+ Treg. In general, rapamycin inhibits innate and adaptive immune functions of TLR‐stimulated human PDC, but enhances the ability of TLR‐7‐stimulated PDC to stimulate CD4+ T cell proliferation and induce CD4+FoxP3+ regulatory T cell generation.