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*
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, and Departments of
Medicine,
Cell Biology and Physiology,
§
Molecular Genetics and Biochemistry, and
¶
Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
Human dendritic cells (DC) have polarized responses to chemokines
as a function 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 rhesus macaque model. We demonstrate that immature and
CD40 ligand-matured monocyte-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
(MIP-1), whereas mature DC switch
expression to CCR7 and respond exclusively to MIP-3ß and 6Ckine.
Mature DC transduced to express a marker gene localized to lymph nodes
after intradermal injection, constituting 1.5% of lymph node DC. In
contrast, cutaneous DC transfected in situ via gene gun were detected
in the draining lymph node at a 20-fold lower frequency. Unexpectedly,
the state of maturation at the time of injection had no influence on
the proportion of DC that localized to draining lymph nodes, as labeled
immature and mature DC were detected in equal numbers. Immature DC that
trafficked to lymph nodes underwent a significant up-regulation of CD86
expression indicative of spontaneous maturation. Moreover, immature DC
exited completely from the dermis within 36 h of injection,
whereas mature DC persisted in large numbers associated with a marked
inflammatory infiltrate. We conclude 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-based
immunotherapy.
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