390
Antigen Presenting Cells (APCs)
binding and uptake of certain pathogen-
derived components are in many cases
linked to DC maturation. During DC mat-
uration, they downregulate their endocytic
capacity. The consequence is that antigen
uptake is no longer possible during migra-
tion to and in the lymph nodes, but only
in peripheral organs. Down-modulation of
en
d
o
c
y
t
o
s
i
si
sa
ch
i
e
v
e
dina
tl
e
a
s
ttw
o
ways: (1) a decrease in surface expres-
sion of several antigen-binding receptors;
(2) inactivation of the GTPases cdc42 and
rac1 widely abolishes macropinocytosis
and phagocytosis.
10.2.1
Macropinocytosis Versus
Phagocytosis
Macropinocytosis
is
a
cytoskeleton-
dependent type of fluid-phase endocyto-
sis that certain growth factors can induce
in macrophages. In immature DCs, how-
ever, macropinocytosis is a constitutive
phenomenon. It allows DCs to sample
large amounts of extracellular fluid in short
periods of time. This is the nonspeciFc
way of DCs to search for antigenic ma-
terial. Antigens that have been captured
by macropinocytosis have access to MIICs
and hence can be loaded onto MHC class
II or CD1 molecules.
Phagocytosis is initiated by the engage-
ment of speciFc surface receptors; hence,
it is to a certain extent antigen-speciFc. Im-
mature DCs phagocytose whole bacteria,
irrespective of whether they are gram-
positive or gram-negative, but also yeast
cells and hyphae. As part of the GALT, in-
terstitial DCs penetrate tight junctions so
that their dendrites have access to bacteria
in the gut lumen.
Immature DCs also internalize cell de-
bris from cells that have undergone cell
death by apoptosis or necrosis. Human
monocyte-derived DCs take up apoptotic
and necrotic bodies derived from B or T
cells, virus-infected apoptotic monocytes,
or tumor cells, including melanoma cells
or various carcinoma cells. Moreover, DCs
have been shown to transport apoptotic
intestinal epithelial cells to T-cell areas of
mesenteric lymph nodes in rats. Phago-
cytosis of apoptotic bodies mainly occurs
through a complex including the scavenger
receptor CD36 and the integrins
α
V
β
5
and
α
V
β
3
. The receptors needed for phagocy-
tosis of necrotic cells are less well deFned.
10.2.2
Receptors for Endocytosis
Receptors
for
the
±
c
portion
of
im-
munoglobulin belong to the prominent
molecules on the DC surface: human
monocyte-derived
DCs
express
mainly
±c
γ
RII and ±c
α
R, LCs express ±c
γ
RI
and ±c
ε
RI, whereas blood DCs are pos-
itive for ±c
γ
RII and ±c
γ
RI. Recently,
a novel member of the Ig superfam-
ily, named Ig-like transcript (ILT)-3 was
found
to
facilitate
antigen
processing
in
DCs,
but
also
in
monocytes
and
macrophages.
In contrast to macrophages, immature
DCs express only the complement re-
ceptors CR3 and CR4, but not CR1 or
CR2. Similar to macrophages, immature
monocyte-derived DCs, blood DCs, and
interstitial DCs of the dermis display high
levels of the MR. The MR not only al-
lows DCs to endocytose a large variety
of bacterial and yeast antigens, but also
desialylated immunoglobulin. Strikingly,
LCs do not express the MR, but Langerin
(CD207), which is also a lectin with man-
nose speciFcity. Unlike the MR, CD207
induces the formation of Birbeck gran-
ules. ±inally, DCs are also very potent
in binding and taking up Hsps, such as
hsp70 and gp96. Recently, CD91, known
as the
α
2
macroglobulin receptor, and
CD40 were described to mediate endocy-
tosis of Hsps of the Hsp70 and Hsp90
previous page 390 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 392 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off