Maturation and trafficking of monocyte-derived dendritic cells in monkeys:Implications for dendritic cell-based vaccines

Human dendritic cells (DC) have polarized responses to chemokines as a func tion of maturation state, but the effect of maturation on DC trafficking in vivo is not known, We have addressed this question in a highly relevant rh esus macaque model. We demonstrate that immature and CD40 ligand-matured mo nocyte-derived DC have characteristic phenotypic and functional differences in vitro. In particular, immature DC express CC chemokine receptor 5 (CCR5 ) and migrate in response to macrophage inflammatory protein-1 alpha (MIP-1 alpha), whereas mature DC switch expression to CCR7 and respond exclusivel y to MIP-3 beta and 6Ckine, Mature DC transduced to express a marker gene l ocalized to lymph nodes after intradermal injection, constituting 1.5% of l ymph node DC. In contrast, cutaneous DC transfected in situ via gene gun we re detected in the draining lymph node at a 20-fold lower frequency. Unexpe ctedly, the state of maturation at the time of injection had no influence o n the proportion of DC that localized to draining lymph nodes,as labeled im mature and mature DC were detected in equal numbers; Immature DC that traff icked to lymph nodes underwent a significant up-regulation of CD86 expressi on indicative of spontaneous maturation, Moreover, immature DC exited compl etely from the dermis within 36 h of injection, whereas mature DC persisted in large numbers associated with a marked inflammatory infiltrate, We conc lude that in vitro maturation is not a requirement for effective migration of DC in vivo and suggest that administration of Ag-loaded immature DC that undergo natural maturation following injection may be preferred for DC-bas ed immunotherapy.