Antigen Presenting Cells (APCs)
371
a peptide-binding groove and, thus, is un-
able to function as an antigen-presenting
molecule. It bears a targeting signal for
MIICs where it accumulates and tran-
siently engages in complexes with classical
class II MHC molecules. HLA-DM has
three important functions (Fig. 5): (1) it
catalytically removes the Ii-derived pre-
cursor peptide CLIP, thereby promoting
peptide loading; (2) it remains bound to
empty class II molecules and prevents
their unfolding as a molecular chaperone;
and(
3
)i
tfun
c
t
ion
sa
sap
ep
t
id
eed
i
to
r
,
as it removes peptides that bind with low
kinetic stability to class II dimers. Conse-
quently, preferentially high-stability class
II peptide complexes are displayed on the
surface of APCs, as long as these cells bear
suf±cient HLA-DM. This principle allows
APCs, once loaded with cognate antigen,
to activate CD4
+
T cells for prolonged pe-
riods of time, even a couple of days after
encounter of antigenic material.
6.2.4
Tetraspan Network
Professional or nonprofessional APCs and
even T cells express proteins, such as
CD9, CD37, CD53, CD63, CD81, CD82,
and CD151, belonging to a family termed
tetraspan
proteins
or
tetraspanins
.T
h
e
nomenclature relates to the fact that all of
them traverse the membrane four times.
It is well established that they are able to
form homo- and heterodimers and thus
form two-dimensional networks in the
membrane. In APCs, tetraspanins form
clusters with various integrins and MHC
molecules. In MIICs, CD82 and CD63
associate with HLA-DM and classical class
II molecules. On the cell surface, CD81,
CD9,
and
CD53
form
microdomains
together with MHC class II and class
I molecules. The function of tetraspan
microdomains may be to increase the local
density of MHC class II peptide complexes
in loading compartments and on the
surface, so that the avidity of an APC–T
cell encounter is increased, thereby raising
the ef±cacy of T-cell activation.
7
Activation of T Cells by APCs
After leaving the thymus, mature T cells
recirculate between blood and peripheral
lymphoid tissue until they recognize an
MHC-peptide complex on the surface of
an APC. T cells that have not yet been
activated via encounter of an antigen are
termed
naive T cells
. In contrast, T cells that
have already contacted MHC molecules
carrying foreign peptide antigens start
to proliferate and differentiate into cells
capable of contributing to the removal of
the antigen. They are termed
effector T cells
.
Effector T cells can be subdivided into
three classes, according to the type of
pathogen that may skew the ef±ciency
of peptide entry into different process-
ing pathways. Peptides from pathogens
that multiply in the cytosol, such as in-
fluenza virus, vaccinia, and
Listeria mono-
cytogenes
, are presented by MHC class
I molecules and activate CD8
+
cytotoxic
T
cells that
kill
infected target
cells.
Pathogens that accumulate in endoso-
mal vesicles of macrophages, such as
mycobacteria or
Leishmania
, facilitate the
differentiation of T
H1
helper cells that ex-
press Fas ligands enabling them to kill
infected macrophages. Extracellular anti-
gen derived from viruses tend to stimulate
the production of T
H2
helper cells that
initiate a humoral immune response by
activating naive B cells to produce neutral-
izing IgM antibodies.
The activation of naive T cells fol-
lowing engagement with MHC–peptide
complexes in APCs constitutes a primary
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