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 (t1/2) 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 t1/2. Here, we have studied CTL activity in response to tumor cells loaded with pMHC that bind the TCR with different t1/2. We observed that the TCR/pMHC t1/2 can differentially regulate CTL effector function during the interaction with tumo... More
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 (t1/2) 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 t1/2. Here, we have studied CTL activity in response to tumor cells loaded with pMHC that bind the TCR with different t1/2. We observed that the TCR/pMHC t1/2 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 t1/2 promoted only partial expression of cytotoxic molecules, short t1/2 induced partial polarization of lytic machinery toward target cells. In contrast, intermediate TCR/pMHC t1/2 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 t1/2 pMHC ligands. These data suggest that there is an optimal TCR/pMHC t1/2 for efficient CTL activity.
