Antigen Presenting Cells (APCs)
391
protein family. These Fndings are intrigu-
ing, as endogenous as well as foreign
Hsps are discussed to mediate matura-
tion of DCs. In particular, the activatory
capacity of necrotic cells has been ascribed
to Hsps
10.2.3
The Adhesion Receptor DC-SIGN
DC-SIGN (DC-speciFc ICAM-3-Grabbing
Nonintegrin), also termed CD209, is a
mannose-binding C-type lectin that is
strongly and selectively expressed on DCs,
irrespective of whether they are immature
or mature.
DC-SIGN recognizes with high afFnity
the adhesion molecule ICAM-2 on vascular
and lymphoid endothelia. ICAM-2 serves
as a rolling counterreceptor, thereby en-
abling DC-SIGN
+
DCstotethertoandroll
along endothelia. This is a prerequisite
for trans-endothelial migration into pe-
ripheral tissues and secondary lymphoid
organs. Thus, one function of DC-SIGN
is to function as a DC-speciFc rolling
receptor.
Upon reaching T cell–rich areas in
secondary
lymphoid
organs,
DC-SIGN
mediates initiation of T cell–dependent
immune responses: it enables transient
DC–T-cell interactions through binding to
ICAM-3, which is expressed on the surface
of naive T cells. In contrast, DC-SIGN does
not bind to the principal ligand of L±A-1,
ICAM-1.
±inally, DC-SIGN functions as an HIV-1
trans-receptor important in the dissemi-
nation of HIV-1. HIV-1 is captured on
DCs present in the periphery by DC-
SIGN, which binds to the HIV-1 coat
protein gp120.
Thus,
HIV-1 is trans-
ported by DCs that migrate into lym-
phoid tissues where DC-SIGN-associated
HIV-1
efFciently
infects
target
CD4
+
T cells.
10.3
Maturation of DCs
The various subtypes of human DCs
described above vary considerably with
regard to the expression of marker proteins
and their behavior in the immature state.
However, as soon as they are subjected
to inflammatory stimuli, they share a
common program, termed maturation,
which transforms immature into mature
DCs that are highly efFcient in priming
and activating T cells. They are by far
more potent than activated macrophages
or B cells in initiating a cellular immune
response. This is mainly due to the fact
that key proteins, for example, MHC
molecules, costimulators, and accessory
molecules,
are
much
more
abundant
on
mature
DCs
than
on
stimulated
macrophages or B cells.
10.3.1
Maturation Stimuli
Immature DCs respond to two types of
maturation stimuli: (1) direct recognition
of pathogens via TLRs and other PPRs;
and (2) inflammatory cytokines and other
exogenous or endogenous mediators that
are secreted during an infection or in
other acute alarm situations (±ig. 11). In
detail, DCs can recognize bacterial pepti-
doglycans, lipopeptides, and mycoplasma
lipoproteins via TLR2, LPS via TLR4, vi-
ral dsRNA via TLR3 and certain DNA
oligonucleotides via TLR9. It should be
emphasized that TLR2 is not present on
the cell surface, but speciFcally recruited
to yeast-containing phagosomes. Likewise,
TLR4 is not compulsory for internalization
of LPS-carrying bacteria. This suggests
that TLRs are involved in discrimination
of microbes and not necessarily in their
uptake. Apart from that, DCs have re-
ceptors in order to sense infections and
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