396
Antigen Presenting Cells (APCs)
The outstanding T-cell priming capacity
of mature DCs is mainly due to the
enhanced surface levels of costimulatory
CD80 and CD86 and adhesion molecules,
but also connected to a rapid relocalization
of antigen-bearing DCs to the T-cell zones
of secondary lymphoid organs. The
in vivo
relevance of DC maturation in T-cell
priming is particularly evident in the
case of CD8
+
T cells. Although there are
examples of direct priming of CTLs by
DCs without the involvement of CD4
+
T
cells, numerous cases have been described,
where CD8
+
naive T cells are dependent
on CD4
+
T-cell help. It was found that
CD40 ligation on DCs by CD40L on CD4
+
T cells was necessary and sufFcient to
confer to DCs the ability to prime CTLs. At
the same time, DCs are rendered mature
(±ig. 13).
This mechanism allows a temporal dis-
sociation of interactions between DCs,
CD4
+
helper T cells, and CD8
+
CTLs:
once licensed by CD4
+
T cells, mature
DCs are competent to prime CD8
+
T cells.
This model, also known as the
license-to-kill
model
bypasses the requirement of a tricel-
lular interaction of DCs, activated helper
T cells and naive CTLs in lymph nodes,
which is rather unlikely to occur. Apart
from helper T cells,
pathogen-derived
products, such as LPS, viruses or apoptotic
bodies carrying CD40L have been shown
to deliver licensing signals to DCs.
10.5.2
T Helper Cell Polarization
In the most recent literature, the issue
of T-helper cell polarization by DCs has
received considerable attention. Various
pathways of regulation are operative. Im-
mature DCs
per se
favor T
H2
polarization,
but they can be reinstructed by the charac-
teristics of the antigen or its accompanying
adjuvant to induce a T
H1
,T
H2
,oranun
-
differentiated T
H0
response (Table 8).
Microbe-derived
pattern
molecules,
such as LPS or CpG oligonucleotides,
drive T
H1
polarization by induction of
IL-12, IL-6, and IL-1
β
secretion through
binding
to
TLRs.
However,
microbial
products
often
need
additional
host-
derived microenvironmental instruction to
Infected
tissue
Tissue
destruction
Immature
DC
Priming of
CD8
+
T cells
Licensed
DC
CD4
+
T cell
CD8
+
T cell
MHC I/
TCR
IL-12
TCR/
MHC II
CD40/
CD40L
B7/
CD28
Fig. 13
The license-to-kill model of DCs. Immature DCs that encounter activated CD4
+
Thelper cells receive a signal through CD40/CD40L engagement. DCs that have received
this signal are able to render cytotoxic CD8
+
T cells highly potent in killing infected target
tissues. Thus, DCs conditioned by Thelper cells bear the license to kill.
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