Antigen Presenting Cells (APCs)
395
during the life cycle of DCs. An immature
DC
exposes
around
10
6
MHC
class
II molecules on the
surface. This is
already more than activated B cells or
macrophages can ever express, however,
5 to 10 times less than in mature DCs.
Several
reasons
account
for
that:
the
efFciency of major proteases involved in
antigen degradation in immature DCs,
for example, cathepsins B and S, is low.
This may be due to comparably high
levels of endogenous protease inhibitors
such as cystatin C and the Ii splice
variant Iip41. Another aspect is that not
all endosomes or phagosomes may have
access to MIICs, where MHC class II
molecules are loaded with peptide. ±inally,
MHC class II–peptide complexes have a
short half-life (
10 h) in immature DCs,
since they are constantly internalized and
transported to recycling endosomes, where
peptide exchange occurs, or is degraded
in lysosomes. Nevertheless, it should be
pointed out that immature DCs are able to
present self- and foreign antigen peptides
to CD4
+
T cells. According to current
concepts, this process serves mainly to
tolerize T cells against self-antigens.
Inflammatory signals activate a program
leading to profound changes in antigen
processing for class II molecules. MHC
c
lassIIb
iosyn
thes
isistrans
ien
t
lyupreg
-
ulated, the activity of processing proteases
increases accompanied by their relocaliza-
tion into MIICs and recycling of class II
molecules ceases widely. ±ollowing pep-
tide loading in MIICs, subsets of class
II molecules associate with the costim-
ulator CD86 and the tetraspanins CD82
and CD63, thereby becoming a part of
multimeric clusters that are transported
to the cell surface. At the cell surface,
class II peptide complexes remain orga-
nized in a multimerized fashion, mainly
associated to tetraspanins. The tetraspan
microdomains, which are strongly upreg-
ulated in mature DCs, not only concentrate
MHC-peptides complexes but also enrich
MHC class II molecules loaded with par-
ticular peptide. This increases the local
avidity to T cells and, hence, increases the
efFcacy of T-cell activation. This is further
supported by the fact that the mature DCs
no longer endocytose class II molecules
so that the latter become rather long-lived.
After 10 to 20 h of maturation, no further
class II molecules are synthesized and the
activity of HLA-DM is strongly downregu-
lated so that peptide loading ceases. Thus,
mature DCs that have reached the T-cell
areas of lymph nodes mainly present those
peptide antigens to CD4
+
T cells that they
have captured before or during induction
of maturation in peripheral tissues.
10.5
T Cell Priming and Polarization
10.5.1
Priming of CD8
+
and CD4
+
T Cells
Several lines of evidence support the con-
cept that DCs are the principal APCs for
T-cell priming. This is based on
in vitro
observations, where DCs were compared
to other APCs for priming alloreactive,
naive T cells or the expansion of naive pre-
cursors from polyclonal populations. ±ur-
thermore, injection of antigen-loaded DCs
induces potent CD4
+
and CD8
+
T-cell pri-
mary responses. By immunofluorescence
on lymph node sections, interactions of
DCs and T cells could be directly visual-
ized. Beyond that, DCs break peripheral
tolerance against transplantation antigens
and tumor antigens. Moreover, the exclu-
sive expression of MHC class II molecules
in DCs was sufFcient for the establishment
of central tolerance through V
β
-speciFc
deletion of T cells by a superantigen pre-
sented by DCs in the thymus medulla.
previous page 395 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 397 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off