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et al., 1993). Another blood-borne population represents mature CD83
DC
(O'Doherty et al., 1994; Thomas et al., 1993; Weissman et al., 1995) possibly
nonlymphoid resident DC in transit to lymphoid tissues. Recently, we have
identi®ed two DC precursor populations in blood that express the DC-speci®c
ICAM-3- and HIV-1-receptor DC-SIGN, but di¨er in CD14 expression (Geij-
tenbeek et al., 2000c); these populations probably represent di¨erent stages of
DC precursors en route to seeding peripheral tissues as immature DC.
DC precursors are recruited from the blood to peripheral tissues constitu-
tively to replenish the tissue or in response to in¯ammation. Tethering to the
blood vessel endothelium is an essential prerequisite for the exit of DC pre-
cursors from the blood, and is necessary for subsequent ®rm adhesion and ex-
travasation. The DC-speci®c adhesion receptor DC-SIGN mediates this initial
tethering of DC-SIGN-positive cells along ICAM-2 (Geijtenbeek et al., 2000c),
an endothelial ligand abundantly expressed on both blood and lymphatic vessels.
The transendothelial migration of DC increases upon activation of endothelial
cells, leading to an increase in the egress of DC precursors, and is mediated by
DC-SIGN/ICAM-2 interactions. DC-SIGN is rapidly up-regulated on mono-
cytes in the presence of GM-CSF and IL-4 (Geijtenbeek et al., 2000b); thus,
DC-SIGN up-regulation by cytokine mediators may induce migration of pre-
cursor DC from blood into the periphery. The presence of DC-SIGN-positive
DC precursors in blood further supports the hypothesis that, under physiologi-
cal circumstances, DC-SIGN/ICAM-2 interactions mediate rolling along endo-
thelial linings and transmigration of DC into the periphery (Geijtenbeek et al.,
2000c). These DC-SIGN-positive DC precursors could be poised to exit the
blood at in¯ammatory sites, allowing rapid recruitment of these cells to sites
where their surveillance function is needed. The high expression of DC-SIGN
on immature DC in the peripheral tissues, and the expression of ICAM-2 on
lymphatic vessels, further supports a central role for the DC-SIGN/ICAM-2
interaction in DC-speci®c migration from blood into the periphery, whether
in¯amed or not, and subsequently of immature DC via the lymph into lym-
phatic tissues.
Navigation of DC from blood into tissues and to their ®nal destination, the
T-cell area of the lymphoid tissues, is governed by the action of chemokines.
Chemokines are a superfamily of chemotactic proteins that can be divided in
four groups on the basis of their cysteine structural motifs. Most chemokines
fall in two families, the CXC group, which is mainly active on neutrophils and
lymphocytes, and the CC group, which is active on multiple subsets of mono-
nuclear cells, including DC.
It is becoming clear that distinct chemokine-chemokine receptor pairs are
responsible for the di¨erent navigational steps of DC. The CC chemokines,
such as IL-8, macrophage in¯ammatory protein (MIP)-1a, and Regulated upon
Activation, Normal T cell Expressed and Secreted (RANTES), induce chemo-
tactic and transendothelial migration of immature DC in vitro. The two main
receptors for these chemokines, CCR1 and CCR5, are expressed by immature
DC; they enable the ®rst step of DC migration from blood into in¯amed tissues
