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Published on: November 28, 2014
PELs and the perforin and granzyme independent mechanism of CTL-mediated lysis
1Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
The central role of CTLs in immunopathology accounts for the increasing interest in deciphering the mechanism whereby they kill at the molecular level. Recent studies show that CTLs have two molecularly distinct lytic mechanisms at their disposal. The first involves the direct effect(s) of the pore-forming protein perforin, possibly in conjunction with granzymes. In recent years, experiments conducted in our laboratory led to an alternative pathway, of receptor-mediated mechanism for CTL killing, involving neither the secretion nor the lytic action of the pore-forming protein perforin or of granzymes. By this mechanism, engagement of a CTL membrane ligand and an apoptosis-inducing target cell surface receptor triggers the disintegration of the CTL-bound target cell. Cross-linking of apoptosis-inducing target cell surface molecules (e.g. Fas), induced upon binding of CTL ligands (e.g. Fas-L), may be required and sufficient to trigger target cell apoptosis. Intracellular lethal signals emanating from the cross-linked intracellular death domain of Fas are postulated.
Insights
Cytotoxic T-lymphocytes (CTLs) kill target cells via perforin/granzyme or a novel receptor-mediated pathway. This alternative mechanism bypasses perforin and granzymes, directly inducing target cell apoptosis through CTL ligand engagement.
Area of Science:
- Immunology
- Cellular Biology
- Molecular Mechanisms of Cell Death
Background:
- Cytotoxic T-lymphocytes (CTLs) play a crucial role in immunopathology.
- Understanding CTL killing mechanisms at the molecular level is of significant interest.
- Two distinct CTL lytic pathways have been identified.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying CTL-mediated cytotoxicity.
- To investigate an alternative, receptor-mediated CTL killing pathway.
- To determine if this alternative pathway involves perforin or granzymes.
Main Methods:
- Experimental investigation of CTL-target cell interactions.
- Analysis of CTL-mediated killing independent of perforin and granzymes.
- Focus on receptor-ligand engagement and subsequent target cell apoptosis.
Main Results:
- A novel CTL killing mechanism was identified, distinct from the perforin/granzyme pathway.
- This alternative pathway involves CTL membrane ligand engagement with target cell surface receptors.
- Cross-linking of apoptosis-inducing molecules (e.g., Fas) on target cells, triggered by CTL ligands (e.g., Fas-L), is sufficient to induce apoptosis.
Conclusions:
- CTLs possess at least two distinct molecular killing mechanisms.
- A receptor-mediated pathway, independent of perforin and granzymes, effectively induces target cell apoptosis.
- Intracellular signaling, potentially via the Fas death domain, mediates target cell destruction in this pathway.
