Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets

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Abstract
Cyclosporin A (CsA) is a potent immuno‐suppressant and is approved for the treatment of various disease conditions. The molecular biological mechanism of CsA has been investigated intensively in T cells and has been shown to involve the intracellular calcineurin pathway. Recently, it was reported that CsA has capacities to affect not only T cells but also antigen‐presenting cells such as B cells and dendritic cells (DCs). DCs are a master regulator of immune responses that have an integral capacity to prime naive T cells. In the present study, we investigated the biological effects of CsA on human peripheral blood DC subsets: CD11c+ myeloid and CD11c− lymphoid subsets. CsA inhibited the up‐regulation of co‐stimulatory molecules induced with or without microbial stimuli and CD40L on both CD11c+ and CD11c− subsets. In addition, CsA negatively regulated the endocytic activity of CD11c+ DC during the immature state. CsA inhibited the interleukin‐12 (IL‐12) production, but augmented the IL‐10 production from the LPS‐stimulated CD11c+ subset, whereas CsA reduced the interferon‐α (IFN‐α) production from the CD11c− subset infected with Sendai virus (SV). Both the LPS‐stimulated CD11c+ subset and SV‐infected CD11c− subset preferentially induced the development of IFN‐γ‐producing T helper‐type 1 (Th1) cells. Pretreatment of these DC subsets with CsA inhibited the Th1 skewing. These findings suggested a DC‐mediated mechanism of immunosupression by CsA.