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CO-STIMULATORY MOLECULES ARE ESSENTIAL FOR T CELL ACTIVATION

Crucially, co-stimulatory molecules act together with


the antigen-specific signals before the T cell is sanctioned
for proliferation. Co-stimulatory and antigen-specific
signals must be present simultaneously on the same cell.
Overall, antigen presentation through MHC class I or
class II molecules can be split into four stages adhesion,
antigen-specific activation, co-stimulation, and cytokine
signaling (see Fig. 7.1).

Multiple cell surface molecules interact


during antigen presentation to T cells

Intercellular adhesion molecules (ICAMs), particularly


ICAM-1 (CD54), interact with the integrin, lymphocyte
functional antigen-1 (LFA-1 or CD11a/CD18), present
on all immune cells.
If mouse cells are transfected with both human MHC
and human ICAM-1, their capacity to act as human APCs
is augmented.
When the T cell encounters the appropriate MHC
moleculepeptide, which happens rarely except during
an ongoing infection, a conformational change in LFA-1
on the T cell, signaled via the TCR, results in tighter
binding to ICAM-1, which results in prolonged cellcell
contact. The joined cells can exist as a pair for long
periods, allowing time for the T cell to proliferate and
differentiate.
The specific MHC moleculepeptideTCR interaction, though necessary, is not sufficient to fully activate the
T cell. A second signal is required, otherwise the T cell
will become unresponsive. This second signal, also
referred to as co-stimulation, is of crucial importance.
Some co-stimulatory molecules that interact with
ligands on the T cells surface are shown in Fig. 7.16.
The most potent co-stimulatory molecules known are
B7s, which are members of the immunoglobulin superfamily molecules; they include B7-1 (CD80) and B7-2
(CD86).

Critical molecules involved in antigen presentation


T cell
CD2

LFA-1

TCR

IL-1
IL-6
TNF!
IL-12
IL-15

p56Lck

CD4

LFA-3
(CD48)

ICAM-1

class II
APC

Several other B7-related molecules are beginning to


emerge.
B7s exist as homodimers on the cell surface. These
proteins are constitutively expressed on DCs, but can be
upregulated on monocytes, B cells, and probably other
APCs.
Upregulation of co-receptors is stimulated by inflammation and by interaction of microbial products with Tolllike receptors (TLRs, see Fig. 6.24) on the APC.
Co-receptors are the ligands for other immunoglobulin
superfamily molecules CD28 and its homolog CTLA-4
(CD152), which is expressed after T cell activation. CD28
is the main co-stimulatory ligand expressed on naive T
cells. CD28 stimulation:
has been shown to prolong and augment the production of IL-2 and other cytokines; and
is probably important in preventing the induction of
tolerance.
Although the CD28B7 interaction is extremely important, CD28 knockout mice do respond to antigen, but
require higher doses, so CD28 triggering is not obligatory, even for naive T cells. In CD28 knockout mice
other co-stimulatory signals probably replace that delivered by CD28B7.
CTLA-4, the alternative ligand for B7, is an inhibitory
receptor limiting T cell activation, resulting in less IL-2
production. Thus CD28, constitutively expressed, initially
interacts with B7, leading to T cell activation. Once this
has peaked, the upregulation of CTLA-4 with its higher
affinity limits the degree of activation because available B7
will interact with CTLA-4 (Fig. 7.17).
Q. What effect would you expect to see in mice that have
the CTLA-4 gene knocked out?
A. They suffer from an aggressive lymphoproliferative disorder,
because they do not inactivate dividing T cells efficiently (see
Fig. 7.17).

Role of CTLA-4 in controlling T cell activation

CD28

activation
division
IFN"
GM-CSF
IL-4
TNF#

B7-1/B7-2
(CD80/CD86)

Fig. 7.16 The molecules involved in the interaction between T


cells and APCs. The various cytokines and their direction of
action are also shown. In humans LFA-3 (CD58) acts as a
ligand for CD2, but in rodents CD48 performs this function.

inactivation
T

CTLA-4

CD28
B7

B7

APC

APC

Fig. 7.17 Before activation, T cells express CD28, which


ligates B7-1 and B7-2 on APCs (e.g. B cells). After activation,
CTLA-4 is expressed, which is an alternative high-affinity
ligand for B7. CTLA-4 ligates B7, so the T cells no longer
receive an activation signal.

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