Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10

Dendritic cell (DC) activation through CD40-CD40 ligand interactions is a k ey regulatory step for the development of protective T-cell immunity and al so plays an important role in the initiation of T-cell responses involved i n autoimmune diseases and allograft rejection. In contrast to previous repo rts, we show that the immunosuppressive drug dexamethasone (DEX) redirects rather than simply blocks this DC activation process. We found that DCs tri ggered through CD40 in the presence of DEX were unable to acquire high leve ls of costimulatory, adhesion, and major histocompatibility complex class I and II molecules and failed to express the maturation marker CD83, whereas antigen uptake was not affected. Moreover, DEX strikingly modified the CD4 0-activated DC cytokine secretion profile by suppressing the production of the proinflammatory cytokine interleukin (IL)-12 and potentiating the secre tion of the anti-inflammatory cytokine IL-10, Accordingly, DEX-exposed CD40 -triggered DCs displayed a decreased T-cell allo-stimulatory potential and a dramatically impaired ability to activate cloned CD4(+) T helper 1(Th1)ce lls. Moreover, interaction between Th1 cells and these DCs rendered the T c ells hyporesponsive to further antigen-specific restimulation. Collectively , our results demonstrate that DEX profoundly modulates CD40-dependent DC a ctivation and suggest that the resulting alternatively activated DCs can be exploited for suppression of unwanted T-cell responses in vivo, (C) 2000 b y The American Society of Hematology.