CD40 Agonist-activated mTORC1 Signaling Synergizes with PD-1 Checkpoint Blockade to Counter T-cell Exhaustion in Chronic Infection

In chronic infection, T-cell exhaustion due to sustained programmed cell death (PD)-1 expression on cytotoxic T lymphocytes (CTLs) is one of the major issues leading to ineffective virus elimination. Programmed cell death ligand-1 (PD-L1) pathway blockade has been found to restore the function of exhausted CTLs during chronic infection. Understanding mechanisms involved in the conversion of CTL exhaustion is essential to improve disease therapy and vaccine protocols. In this commentary, we focus on the mechanism by which triggering CD40 signal alone can convert CTL exhaustion and synergize with PD-1 checkpoint blockade in rescuing exhausted CTLs.