As a consequence of multi-hit delivery, single CTLs are capable of eliminating multiple antigenic target cells in vitro and in vivo, ranging from 1 up to 20 kills per CTL and day, as estimated from bulk killing assays and mathematical modeling 6, 7. ![]() CTL and natural killer (NK) cells can bind to and attack more than one target cell sequentially 3, 4, 5. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.Ĭytotoxic T lymphocytes (CTLs) execute effector function by a cyclic process of transient cell–cell interaction and paracrine delivery of cytotoxic effector molecules to target cells, followed by target cell death 1, 2. ![]() In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. ![]() In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process.
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