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