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Reactive Oxygen Species in CTL-mediated Cell Death: from Mechanism to Applications

Final Report Summary - CTLANDROS (Reactive Oxygen Species in CTL-mediated Cell Death: from Mechanism to Applications)

Using a large cross disciplinary approaches, the results obtained from this proposal have significantly advanced our understanding of the function of ROS during the process of immune elimination of target cells. We can confidently say that not only ROS are active effectors of the death process but also they inform the immune effector cells on the status of their targets. The biogenesis of these ROS is centered on the disruption of respiratory chain complex I. Complex I disruption is shared by three different cell death pathways (GA, GB, caspase 3) and conserved from bacteria to mammals. Our results uncovered a rather unanticipated required step in cell death, meaning the mitochondrial entry
of cytotoxic molecules through a non-canonical import pathway. In fact we found that granzyme enter the mitochondrial matrix through Sam50 and Tim22 channel with the help of the mitochondrial Hsp70. Superoxide anions generated from the cleavage of complex I subunits potentiate bid/Bax/Bak dependent apoptogenic factors release, oligonucleosomal DNA fragmentation and the lysosomal membrane rupture. We found that the redox status of the target cells is a discriminating criteria for cytotoxic immune cell attack. The differential redox status of the target cell impact on their ability to be engaged by immune effector cells. Oxidized target cell are less killed and reciprocally less
oxidized targets, such as cancer stem cells, are better killed. The molecular understanding of this differential killing of the cancer stem cell uncover rather very novel insight such as the impact on the mitochondrial dynamic and contact with the ER on the surface glycome expression and killer cell engagement. Finally, our results clearly indicate that the modulation of the redox signaling taking place during immune elimination of target cells can impact not only the outcome of the death process but in addition the behavior of the immune effector cells. Together, this make this redox signalling an even more appealing therapeutic target.