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 key regulatory step for the development of protective T-cell immunity and also plays an important role in the initiation of T-cell responses involved in autoimmune diseases and allograft rejection. In contrast to previous reports, we show that the immunosuppressive drug dexamethasone (DEX) redirects rather than simply blocks this DC activation process. We found that DCs triggered through CD40 in the presence of DEX were unable to acquire high levels 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 CD40-activated DC cytokine secretion profile by suppressing the production of the proinflammatory cytokine interleukin (IL)-12 and potentiating the secretion of the anti-inflammatory cytokine IL-10. Accordingly, DEX-exposed CD40-triggered DCs displayed a decreased T-cell allostimulatory potential and a dramatically impaired ability to activate cloned CD4(+) T helper 1 (Th1) cells. Moreover, interaction between Th1 cells and these DCs rendered the T cells hyporesponsive to further antigen-specific restimulation. Collectively, our results demonstrate that DEX profoundly modulates CD40-dependent DC activation and suggest that the resulting alternatively activated DCs can be exploited for suppression of unwanted T-cell responses in vivo.
Rea
D
D
Department of Immunohematology and Blood Bank and the Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. d.g.rea@immunohematology.medfac.leidenuniv.nl
van Kooten
C
C
van Meijgaarden
K E
KE
Ottenhoff
T H
TH
Melief
C J
CJ
Offringa
R
R
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003907:Dexamethasone / Q000276:immunology* / Q000494:pharmacology; D005938:Glucocorticoids / Q000276:immunology* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D015735:Mifepristone / Q000276:immunology / Q000494:pharmacology
D019013:CD40 Antigens; D005938:Glucocorticoids; D006727:Hormone Antagonists; D016753:Interleukin-10; D015735:Mifepristone; D003907:Dexamethasone