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Molecular mechanisms of lymphocyte-mediated killing
J D Young1, C C Liu, P M Persechini
1Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021.
Abstract:
Lymphocytes kill tumor cells and other target cells by a contact-dependent mechanism. Killer lymphocytes acquire cytoplasmic granules upon lymphokine stimulation and these granules in turn contain potent cytotoxic mediators, some of which have been characterized recently. These include (i) a pore-forming protein (perforin) of 70 kDa that polymerizes into transmembrane tubules in the presence of calcium and that is structurally related to the terminal components (C5b-6, C7, C8 and C9) of the complement cascade, (ii) a cytokine related to tumor necrosis factor and lymphotoxin that causes DNA fragmentation in target cells, and (iii) a family of serine esterases presently without any known function. The relevance of these mediators in lymphocyte-mediated killing is currently being investigated. The identification and characterization of additional putative mediators of cytotoxicity in the future will undoubtedly provide us with a better understanding of the molecular basis of cell-mediated killing.
Insights
Killer lymphocytes use cytotoxic mediators like perforin and cytokines to eliminate tumor cells. Further research into these molecules will clarify the mechanisms of cell-mediated killing.
Area of Science:
- Immunology
- Cell Biology
Background:
- Lymphocytes are crucial for immune surveillance, eliminating tumor cells via contact-dependent mechanisms.
- Cytotoxic lymphocytes (killer cells) develop cytoplasmic granules containing potent mediators upon stimulation.
Purpose of the Study:
- To identify and characterize the cytotoxic mediators within killer lymphocyte granules.
- To understand the molecular basis of cell-mediated cytotoxicity.
Main Methods:
- Characterization of proteins within cytotoxic granules.
- Investigating the function of identified mediators in target cell lysis.
Main Results:
- Identified a pore-forming protein (perforin) structurally related to complement components.
- Identified a cytokine (similar to TNF and lymphotoxin) inducing target cell DNA fragmentation.
- Identified a family of serine esterases with unknown function.
Conclusions:
- Perforin and specific cytokines are key mediators in lymphocyte-induced cell killing.
- Further investigation of these and other granule-associated molecules is essential for understanding cell-mediated immunity.