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CTX-B inhibits CTL cytotoxicity and cytoskeletal movements
S Sugawara1, H R Kaslow, G Dennert
1Department of Microbiology, University of Southern California School of Medicine, Los Angeles 90033.
Abstract:
Binding of cytotoxic T lymphocytes (CTL) to specific targets induces cytoskeletal movements in the effector cell followed by delivery of the lethal hit which ultimately results in target cell lysis. The question whether movement of the cytoskeleton in CTL are obligatory for delivery of the lethal hit is not resolved. Here we report that the CTX-B subunit of cholera toxin which is devoid of the catalytic CTX-A subunit inhibits CTL function. Inhibition was found not to be due to interference with TCR expression, CTL-target conjugate formation, target induced transmembrane signalling or secretion of BLT-esterase. CTX-B however does interfere with F-actin patch formation at the effector target binding site and inhibits reorientation of the microtubule organizing center and Golgi apparatus towards the target binding site. It is concluded that interference with cytoskeletal movements is responsible for inhibition of cytolysis pointing to an important role of the cytoskeleton in the lytic reaction.
Insights
Cholera toxin B subunit (CTX-B) inhibits cytotoxic T lymphocyte (CTL) function by disrupting essential cytoskeletal movements. This interference with F-actin, microtubule organizing center, and Golgi apparatus reorientation blocks the lethal hit delivery, proving the cytoskeleton
Area of Science:
- Immunology
- Cell Biology
- Toxicology
Background:
- Cytotoxic T lymphocytes (CTLs) eliminate target cells through a process involving cytoskeletal rearrangement and lethal hit delivery.
- The precise role of cytoskeletal dynamics in CTL-mediated cytolysis remains incompletely understood.
Purpose of the Study:
- To investigate the role of the cytoskeleton in CTL function.
- To determine if the CTX-B subunit of cholera toxin affects CTL-mediated cytotoxicity.
Main Methods:
- Assessed CTL function inhibition by CTX-B.
- Evaluated TCR expression, conjugate formation, transmembrane signaling, and BLT-esterase secretion.
- Examined F-actin patch formation and reorientation of microtubule organizing center and Golgi apparatus.
Main Results:
- CTX-B inhibited CTL function without affecting TCR expression, conjugate formation, signaling, or BLT-esterase secretion.
- CTX-B interfered with F-actin patch formation at the effector-target interface.
- CTX-B inhibited the reorientation of the microtubule organizing center and Golgi apparatus towards the target.
Conclusions:
- Cytoskeletal movements are crucial for the delivery of the lethal hit by CTLs.
- Interference with cytoskeletal dynamics, as demonstrated by CTX-B, inhibits CTL-mediated cytolysis.
- The cytoskeleton plays an essential role in the lytic function of cytotoxic T lymphocytes.