Article Figures & Data
Figures
- Figure 1
T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1. Depicted are various ligand-receptor interactions between T-cells, APCs and cancer cells that regulate the T-cell response to antigen. Activation of T-cells is a two-step process that requires recognition of specific peptides presented by MHC on the surface of cancer cells through their TCR, as well as a co-regulatory signal delivered by the CD28 family of receptors (the so-called immune checkpoints). The co-regulatory signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T-cell. In the absence of this signal (even in the presence of a target peptide), T-cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T-cells on) or inhibitory (switching them off). CTLA-4 and PD-1 deliver inhibitor signals. CTLA-4 negatively regulates T-cell activation by binding to B7 molecules (CD80/86) on the surface of APC or tumor cell. Conversely, when these B7 molecules bind to CD28 they generate the opposite effect, activating signals. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. APC, antigen-presenting cell (dendritic cell, macrophage or any cell that expresses antigen); TCR, T-cell receptor; MHC, major histocompatibility complex.
