The duration of TCR/pMHC interactions regulates CTL effector function and tumor-killing capacity

Effector CTL contribute to tumoral immunity by killing tumor cells through secretion of cytotoxic granules and cytokines. Activation of CTL requires specific recognition of cognate peptide-MHC-I (pMHC) complexes on the tumor cell surface by the CTL TCR. It has been suggested that the half-life (t _1/2) of the TCR/pMHC interaction modulates the activation of naïve CD8⁺ T cells; however, it remains unknown whether CTL effector function can also be regulated by the TCR/pMHC t_1/2. Here, we have studied CTL activity in response to tumor cells loaded with pMHC that bind the TCR with different t_1/2. We observed that the TCR/pMHC t_1/2 can differentially regulate CTL effector function during the interaction with tumor cells and defines the nature of anti-tumoral CTL responses in vivo. Although prolonged TCR/pMHC t_1/2 promoted only partial expression of cytotoxic molecules, short t_1/2 induced partial polarization of lytic machinery toward target cells. In contrast, intermediate TCR/pMHC t_1/2 induced strong expression of cytotoxic molecules, efficient polarization of lytic machinery and subsequent release of toxic granules by CTL that killed tumor cells. Consistently, efficient in vivo CTL-mediated tumor clearance was only observed for tumors expressing intermediate t_1/2 pMHC ligands. These data suggest that there is an optimal TCR/pMHC t_1/2 for efficient CTL activity.