386
Antigen Presenting Cells (APCs)
same time, HLA-DO acts as a cochap-
erone of HLA-DM, which is particularly
relevant at the low pH found in lysoso-
mal MIICs of B cells. Thus, by limiting
the catalytic function of HLA-DM in all
but the most acidic MIICs, HLA-DO ap-
pears to selectively promote loading and
presentation of antigenic peptides derived
from proteins internalized through the
BCR. The rationale is that very low pH,
a high redox potential, and a high abun-
dance of proteases, typical characteristics
of lysosomal MIICs, are required for efF-
cient processing of antigens tightly bound
to BCRs.
Strikingly, the capacity of B cells to
present
antigen
to
helper
T
cells
is
controlled via differential expression of
HLA-DO in quiescent B cells as com-
pared to activated B cells in germinal
centers. In peripheral blood B cells, 50
to 100% of HLA-DM is associated to
HLA-DO. This leads to inefFcient CLIP
removal, and hence to high surface lev-
els of MHC class II-CLIP complexes and
to a reduced capacity to process self-
or foreign antigen. The conclusion is
that due to the comparably high abun-
dance of HLA-DO, peripheral B cells are
reduced in their potential to present for-
eign antigen. The role of class II-CLIP
complexes, as typical representatives of
self, in peripheral tolerance induction
with regard to self-reactive T cells has to
be elucidated.
In germinal centers, however, HLA-
DO is markedly downregulated so that
CLIP is efFciently released from MHC
class II molecules and antigenic peptides
derived from internalized BCR–antigen
complexes
have
access
to
the
bind-
ing
cleft
of
class
II
molecules.
As
20
to
30%
of
HLA-DM
is
still
as-
sociated to HLA-DO, peptide receptive
‘‘empty’’ class II molecules are chaper-
oned by HLA-DM–HLA-DO complexes
until BCR-mediated uptake of foreign
antigen occurs. In summary, regulated
HLA-DO expression allows optimization
of antigen processing and presentation
to helper T cells in germinal centers
during the development of humoral im-
mune responses.
10
Dendritic Cells (DCs)
Dendritic cells (DCs) represent a highly
heterogeneous population of APCs, at
t
h
es
am
et
im
eb
e
i
n
gt
h
em
o
s
tp
o
t
e
n
t
APCs. They are bone marrow–derived
and reside in most peripheral tissues
as
sentinels
of
the
adaptive
immune
system. As DCs, similar to cells of the
innate immune system, express various
types of TLRs that mediate recognition
of
microbial
danger
motifs,
DCs
are
also most critical in bridging innate and
adaptive immunity.
DCs are specialized for the uptake,
transport, processing, and presentation of
antigens to T cells. Any encounter with mi-
crobial products or tissue damage initiates
the migration of DCs out of peripheral
tissues to lymph nodes and their differ-
entiation into the mature state. Mature
DCs express strongly upregulated levels
of MHC and costimulatory molecules so
that, in lymph nodes, DCs can trigger an
immune response by any T cell with a re-
ceptor that is speciFc for MHC-foreign
peptide complexes on the DC surface.
Since subsets of DCs are constantly carry-
ing self-antigens into lymph nodes without
receiving a maturation stimulus, DCs are
thought to play a major role in the mainte-
nance of peripheral tolerance against self
as well.
previous page 386 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 388 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off