Cytotoxic T lymphocyte perforin and Fas ligand working in concert even when Fas ligand lytic action is still not detectable

Summary The reason(s) why individual cytotoxic T lymphocytes (CTL) possess a fast‐acting, perforin/granzyme‐mediated, as well as a much slower, Fas ligand (FasL) ‐driven killing mechanism is not clear, nor is the basis for wide variations in killing activity exhibited by individual CTL, ranging from minutes to hours. We show that perforin expression among individual, conjugated CTL varies widely, which can account for the heterogeneity in killing speeds exhibited by individual CTL. Despite a 2‐hr lag in FasL‐based killing, CTL lytic action is enhanced when the two mechanisms operate in concert. This is explained by finding that the two pathways in fact are jump‐started simultaneously with the lag in FasL lytic action reflecting pre‐lytic caspase‐8 activation and BH3‐interacting domain (BID) cleavage. The complementary action of the two lytic pathways, co‐expressed at varying levels among individual CTL, facilitates the lytic action of late‐stage poor perforin‐expressing CTL, ensuring optimal cytocidal action throughout the CTL response.