392
Antigen Presenting Cells (APCs)
Immature DC
Mature DC
Activated
CD4+ T cells
LPS,
dsRNA
proteoglycan
CpG
IL-12
TNF-
a
IL-1
b
IL-6
MHC I
MHC II
CD40
ICAM-1
ICAM-1
MHC II
CD40
MHC I
CD86
CD80
CD80
Fig. 11
Maturation of dendritic cells (DCs).
Several microbial signals, including LPS, dsRNA,
proteoglycan, and CpG, or the encounter of
activated T helper cells induces the mature
phenotype. Mature DCs strongly upregulate
MHC, costimulatory and adhesion molecules
and secrete the proinflammatory cytokines IL-12,
IL-6, IL-1
β
,andTNF-
α
.
danger indirectly, via binding of TNF-
α
,IL-
1
β
,orPGE
2
, whose secretion is triggered
by pathogens.
Moreover, whole viruses or bacteria dec-
orated with immunoglobulins induce DC
maturation via binding to FcR, including
Fc
γ
RI, Fc
γ
RIII, and Fc
γ
R. Even more im-
portantly, activated CD4
+
T cells provide
a strong stimulus via CD40L that triggers
CD40 of DCs. This signal appears to be es-
sential for conditioning DCs in such a way
that they are able to fully activate certain
types of CD8
+
CTLs.
There is accumulating evidence that
cell death gives rise to signals that ren-
der DC mature, as well. In particular,
necrosis induces DC maturation, however,
the mediators of this activation are still
unknown. Apoptotic cells, at least after
heat stress, are also capable of stimu-
lating immature DCs. Nucleotides, such
as ATP and UTP, and Hsps, including
gp96, Hsp90, and Hsc70 are liberated ex-
tensively in the course of necrosis and
have been proposed to function as danger
signals being able to trigger DC differenti-
ation. However, contaminations with LPS
have been implicated in this context, so
that it is doubtful, as yet, whether Hsps
p
e
rs
eo
rH
s
p
-
LPSc
om
p
l
e
x
e
sh
a
v
ein
-
duced DC maturation. Moreover, Hsp60
and Hsc70 have been described to acti-
vate macrophages through a CD14/TLR4
complex, but receptors on DCs are not
characterized, yet.
10.3.2
The Danger Hypothesis
The model of self–nonself discrimination
foresees that the baseline state of the
immune system is ‘‘OFF.’’ To initiate a
cellular immune response, the key play-
ers, namely, APCs and T cells have to
be activated. T cells get activated by the
encounter of mature APCs. Such mature
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