Immune checkpoints: regulators of the immune system.
The immune system is a finely tuned temporal balance of pro- and
anti-inflammatory signals that allow for appropriately timed
inflammatory responses with subsequent resolution. As such, immune
system stimulation is balanced by numerous pathways designed to guard
against excessive activation and prevent unnecessary damage. Besides the
well-known Tregs, which allow immune tolerance and prevention
autoimmunity through suppression of CD8 T-lymphocytes, several
additional regulatory molecules have been increasingly recognized as
having a pivotal role.28-30 PD-1 and CTLA-4
(Table 1 ) are two examples of these regulators and are known as
immune checkpoint molecules. During the activation of T-lymphocytes,
stimulation of CD28 (expressed on T-lymphocytes) by B7 (expressed on
APCs) induces T-lymphocytes to produce CTLA-4, a CD28 homolog expressed
in low levels on resting T-lymphocytes.27 Upon
T-lymphocyte activation, CTLA-4 moves from intercellular stores to the
T-lymphocyte surface where APC interaction
occurs.27,31,32 CTLA-4 has a much higher binding
affinity for B7, but does not produce a stimulatory signal or even an
inhibitory signal,32-35 instead competing with CD28
for B7, in effect reducing activating signals to the T-lymphocyte,
resulting in anergy of immature/ naïve T-lymphocytes, and dampening the
cytotoxic T-lymphocyte immune response.8 Moreover,
regulatory T-lymphocytes constitutively express CTLA-4, thus potentially
contributing to these cells’ ability to provide suppressive
function.7
PD-1 is a glycoprotein receptor expressed on T-lymphocytes, activated
B-lymphocytes, natural killer cells, monocytes, and some dendritic
cells, while its major ligands (PD-L1 and PD-L2) are found on
B-lymphocytes, dendritic cells, macrophages, as well as
non-hematopoietic cells, such as vascular endothelial cells, neurons,
and certain epithelial cells.36 Though PD-L2 has a
more potent affinity for PD-1 compared to PD-L1, it is expression
repertoire is much more limited, leaving its role in tumor immunity
unclear.37 If T-lymphocytes experience simultaneous
binding of the TCR and PD-1, the interaction of PD-1 with PD-L1
generates signals that prevent phosphorylation of
phosphatidylinositol-3-kinase (PI3K) and downstream Akt, ultimately
resulting in early termination of TCR signaling and blockade of
T-lymphocyte proliferation, cytokine production, cytolytic function, and
impaired T-lymphocyte survival.6,38 Therefore, PD-1
expression is a hallmark of T-lymphocyte exhaustion, which occurs during
chronic infection and cancer, and is characterized by decreased cytokine
expression and effector function of mature effector
T-lymphocytes.39 In addition to the effects on
T-lymphocyte, PD-1 signaling has a variety of additional effects -
inhibition of macrophages and dendritic cell (DC) responses and blockade
of the synthesis and secretion of IL-2, a cytokine crucial in
T-lymphocyte proliferation and differentiation.40-43