Immunosuppressive agents mediate reduced allostimulatory properties of myeloid-derived dendritic cells despite induction of divergent molecular phenotypes

Abstract

Immunosuppressive drugs such as glucocorticoids (dexamethasone (Dexa)), cyclosporin A (CsA) and tacrolimus (Tacro) have been shown to impair differentiation and/or function of immunostimulatory dendritic cells (DC(ims)). Phenotypes and functions of the resultant myeloid dendritic cells, however, have not yet been thoroughly elucidated. We show here that all DC subsets generated by treatment with immunosuppressive agents exhibited considerably reduced allostimulatory properties as measured in the primary mixed lymphocyte reaction (tacrolimus>cyclosporin A>dexamethasone, used at equimolar concentrations). In the MLR, all these DC subsets furthermore inhibited secretion of the T-helper type 1 cytokine IFN-gamma; in addition, DC-Tacro and, less so, DC-CsA induced the T-helper type 2 cytokine IL-4. Upon FACS analysis, DC-Tacro and DC-CsA exhibited phenotypic features similar to DC(ims). In addition, DC-CsA and, to a smaller extent, DC-Tacro were characterized by increased mRNA expression of the novel costimulatory molecule B7-H2 (ICOS-ligand). In contrast, dexamethasone induced the generation of DC characterized by decreased expression of CD83 and CD86, by de novo expression of plasmacytoid and myeloid cell markers CD123 and CD14, respectively, and by sustained expression of Toll-like receptor 2. Interestingly, activation of DC-Dexa with a specific TLR2 ligand induced a strong up-regulation of IL-10 along with TNF-alpha and IL-6, a combination of cytokines that allow amplification of regulatory DC populations. In conclusion, myeloid DC induced by dexamethasone as well as by CsA or tacrolimus show reduced allostimulatory properties; however, they are equipped with different molecular repertoires to exert these functions.