Antigen Presenting Cells (APCs)
373
being presented by the APC; in those cases
in which the T cell recognizes a cognate
MHC-peptide ligand, a conformational
change in LFA-1 increases its af±nity for
ICAM-1 or ICAM-2 of the APC. This
phenomenon allows that the T cell–APC
contact can persist for several days, so
that a naive T cell can proliferate and
become an effector T cell. In the majority of
encounters, the T cell will not recognize an
appropriate peptide antigen and separates
from APCs, keeping on migrating through
the lymph node. Thus, the transient nature
of binding of naive T cells to APCs
via adhesive interactions is crucial in
the sampling of large numbers of MHC
molecules and APCs.
7.2
Costimulatory Molecules
MHC–peptide complexes expressed on
APCs are recognized by ligation of a cor-
responding T-cell receptor on the T-cell
side. This interaction can be viewed as a
±rst signal and it is critical for the antigen-
speci±city of a cellular immune response.
However, in order to trigger clonal expan-
sion and differentiation of a naive T cell,
a second or costimulatory signal delivered
by the same APC is required.
The best-studied costimulatory mole-
cu
lesso
le
lyexp
ressedbyAPCsa
reB7
.1
(CD80) and B7.2 (CD86). Both are homod-
imeric members of the Ig superfamily.
Both B7 molecules share a common re-
ceptor on T cells, CD28. Ligation of CD80
or CD86 by CD28 costimulates the clonal
expansion of naive T cells. Lack of B7
molecules abrogates T-cell proliferation.
Other costimulatory molecules on APCs
are the TNF family member CD40 and
4-1BBL, which bind to CD40 ligand and
4-1BB (CD137) on the T-cell side, respec-
tively. Both pairs of molecules are induced
upon B7/CD28-mediated activation and
function in sustaining the development
of a full T-cell response. Notably, not
only does the T cell receive a signal via
the CD40/CD40L engagement but the
APC also receives a signal. The best-
characterized case is the conditioning of
developing DCs via the engagement of ac-
tivated CD4
+
helper T cells, so that the DC
gains the capacity to fully activate CD8
+
cytotoxic T cells (‘‘license-to-kill model’’; cf
Sect. 10.5.1.).
Activated T cells express an additional
receptor for B7 molecules, denoted as
CTLA-4, a homolog of CD28. However,
CTLA-4 has a manyfold higher af±nity
to
B7
than
CD28
and
transmits
an
inhibitory signal to T cells. Thus, CTLA-
4 upregulation on the surface of T cells
serves to downregulate proliferation and
cytokine secretion of activated T cells.
A
further
CD28-like costimulator
is
ICOS, which recognizes LICOS produced
on activated B cells, monocytes, and DCs.
ICOS is poorly investigated so far – it is
only known to induce IL-10 secretion of
activated T cells.
The physiological relevance of the in-
volvement of costimulatory molecules is
to prevent destructive immune responses
in the absence of signals mediated by
pathogens, for example, responses against
self-tissues. This is accomplished through
the limitation that APCs express costimu-
latory B7 molecules only upon receiving
danger signals from bacterial or viral
products or equivalent proinflammatory
signals. Consequently, naive T cells be-
come effector T cells only when they
receive signal 1 and signal 2 from the
same APC. When signal 2 is lacking, the
T cell is rendered anergic. Anergy means
that the T cell becomes refractory to sig-
nals, even when signal 1 has been sent by
professional APCs.
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