Role of PD-1/PD-L1 crosstalk on inhibition of T-cell activation and proliferation through blockade of PI3K/Akt/mTOR signaling pathway

Activation, differentiation, and proliferation of T-cells are the major parts of critical defense mechanisms that strengthen immune surveillance. Many crucial underlying mechanisms that act on the initiation of T-cell activation, survival, and proliferation. PI3K/Akt/mTOR signaling pathway is one of the key mechanisms that potentially acts on T-cell activation and growth through numerous pathways. However, PD-1 is the inhibitory receptor, present on the surface of T-cells and other immune cells, that inhibits excessive activation of T-cells to avoid autoimmunity. PD-1/PD-L1 crosstalk strongly inhibits T-cell proliferation through the prevention of the action of PI3K/Akt/mTOR cascade. Additionally, the PD1/PD-L1 axis induces the development of regulatory T-cells (Treg) and downregulates glucose transporter 1 (GLUT1) expression via blockade of PI3K/Akt/mTOR machinery, and leads to cell cycle arrest of T-cell occurs. Therefore, inhibition of PD-1/PD-L1 is the breakthrough to restore the action of the PI3K/Akt/mTOR axis to facilitate T-cell activation and proliferation. In this review, we demonstrate multiple mechanisms of PD-1/PD-L1 crosstalk on inhibition of the PI3K/Akt/mTOR signaling pathway.