Science: Reveal how cytotoxic T cells are reloaded with weapons and carry out multiple "kills"

Cytotoxic T cells (CTL) are important cells in the immune system that can recognize and destroy cancer cells and virus- infected cells
.
This killing is mediated by the release of specialized cytolytic proteins, including perforin and granzyme B, which come from stored secretory granules
.

Cytotoxic T cells (CTL) are important cells in the immune system that can recognize and destroy cancer cells and virus- infected cells
.
This killing is mediated by the release of specialized cytolytic proteins, including perforin and granzyme B, which come from stored secretory granules
.
Immune infection

One feature that makes CTLs a particularly effective killer is that they can perform continuous, continuous killing, with a single CTL attacking multiple targets, one after another
.
Although the quality of mitochondria is correlated with the anti-tumor activity of CTL, CTL exhibits an increased dependence on glycolysis, which indicates a decreased dependence on mitochondrial respiration
.
It is not clear whether, how, or why mitochondria contribute when CTL seeks, recognizes, and kills their targets
.

One feature that makes CTLs a particularly effective killer is that they can perform continuous, continuous killing, with a single CTL attacking multiple targets, one after another
.
Although the quality of mitochondria is correlated with the anti-tumor activity of CTL, CTL exhibits an increased dependence on glycolysis, which indicates a decreased dependence on mitochondrial respiration
.
It is not clear whether, how, or why mitochondria contribute when CTL seeks, recognizes, and kills their targets
.

USP30 (ubiquitin carboxyl-terminal hydrolase 30) is a deubiquitinase known to inhibit mitochondrial autophagy.
It was identified as a CTL killer in a large-scale screening of single-gene deletion mice Sexual regulator
.
These results indicate that mitochondria may play a previously unrecognized role in the biological characteristics of CTL
.
Therefore, in a new study, researchers from the University of Cambridge and the University of Dundee in the United Kingdom obtained CTL from USP30-deficient mice to study the nature of this defect and understand how it affects the lethality of CTL
.
The relevant research results were published in the Science Journal on October 15, 2021, with the title of the paper "Mitochondrial translation is required for sustained killing by cytotoxic T cells"
.

USP30 (ubiquitin carboxyl-terminal hydrolase 30) is a deubiquitinase known to inhibit mitochondrial autophagy.
It was identified as a CTL killer in a large-scale screening of single-gene deletion mice Sexual regulator
.
These results indicate that mitochondria may play a previously unrecognized role in the biological characteristics of CTL
.
Therefore, in a new study, researchers from the University of Cambridge and the University of Dundee won the CTL from USP30-deficient mice to study the nature of the defect and how it affects the destruction of CTL won CTL from USP30-deficient mice to study the nature of this defect and understand how it affects the lethality of CTL
.
The relevant research results were published in the Science Journal on October 15, 2021, with the title of the paper "Mitochondrial translation is required for sustained killing by cytotoxic T cells"
.
"Mitochondrial translation is required for sustained killing by cytotoxic T cells"
.

 

 

 

T cell development in USP30-deficient mice is not affected
.
However, once activated, CTL produced by CD8+ T cells have acute mitochondrial loss and impaired lethality
.
The cytotoxicity of USP30-deficient CTL decreased over time, indicating that its sustained lethality is defective
.
Although Usp30-/- CTL loses mitochondria and reduces oxidative phosphorylation, their migration ability, signal transmission and secretion are all required for CTL's lethality
.
However, these authors found that Usp30-/- CTL secreted particles decreased in size, and the newly synthesized key cytolytic protein, the intermediate product of perforin and granzyme B, also decreased
.
This indicates that there are inherent defects in the de novo protein synthesis process, and the de novo protein synthesis is necessary for sustained killing
.

T cell development in USP30-deficient mice is not affected
.
However, once activated, CTL produced by CD8+ T cells have acute mitochondrial loss and impaired lethality
.
The cytotoxicity of USP30-deficient CTL decreased over time, indicating that its sustained lethality is defective
.
Although Usp30-/- CTL loses mitochondria and reduces oxidative phosphorylation, their migration ability, signal transmission and secretion are all required for CTL's lethality
.
However, these authors found that Usp30-/- CTL secreted particles decreased in size, and the newly synthesized key cytolytic protein, the intermediate product of perforin and granzyme B, also decreased
.
This indicates that there are inherent defects in the de novo protein synthesis process, and the de novo protein synthesis is necessary for sustained killing
.
These authors found that Usp30-/- CTL secreted particles decreased in size, and the newly synthesized key cytolytic protein, the intermediate product of perforin and granzyme B, also decreased
.
This indicates that there are inherent defects in the de novo protein synthesis process, and the de novo protein synthesis is necessary for sustained killing
.

Monitoring protein translation found that Usp30-/-CTL protein synthesis was significantly reduced
.
By using mass spectrometry to understand whether protein translation defects affect all proteins equally, they found that only a part of the cytoplasmic proteins were affected, including the key mediators of the killing reaction: granzyme B, perforin and tumor necrosis factor-α (TNF-α) and interference Element-γ (IFN-γ)
.
CTL does not require effective oxidative phosphorylation to maintain their cytotoxicity
.
However, the use of doxycycline or chloramphenicol selectively inhibits mitochondrial translation and weakens the translation of cytolytic proteins, indicating that mitochondrial translation plays an important role in sustained CTL killing
.

Monitoring protein translation found that Usp30-/-CTL protein synthesis was significantly reduced
.
By using mass spectrometry to understand whether protein translation defects affect all proteins equally, they found that only a part of the cytoplasmic proteins were affected, including the key mediators of the killing reaction: granzyme B, perforin and tumor necrosis factor-α (TNF-α) and interference Element-γ (IFN-γ)
.
CTL does not require effective oxidative phosphorylation to maintain their cytotoxicity
.
However, the use of doxycycline or chloramphenicol selectively inhibits mitochondrial translation and weakens the translation of cytolytic proteins, indicating that mitochondrial translation plays an important role in sustained CTL killing
.

 

 

Mitochondria regulate the continuous killing of CTL.
Picture from Science, 2021, doi:10.
1126/science.
abe9977
.

Mitochondria regulate the continuous killing of CTL.
Picture from Science, 2021, doi:10.
1126/science.
abe9977
.

 

 

How does mitochondrial translation selectively affect the translation of cytolytic proteins and regulate the killing ability of CTL? Neither the activation of mTOR signal nor the integrated stress response caused the loss of Usp30-/-CTL cell translation and killing
.
However, in the CTL eliminated by USP30 and the CTL treated with doxycycline, the expression of metabolic enzymes that can double as RNA-binding protein (RBP) has changed
.
Therefore, these findings indicate that the post-transcriptional regulation of RBP, a phenomenon well described in CTL, may regulate the selective down-regulation of protein synthesis detected after the loss of USP30
.

How does mitochondrial translation selectively affect the translation of cytolytic proteins and regulate the killing ability of CTL? Neither the activation of mTOR signal nor the integrated stress response caused the loss of Usp30-/-CTL cell translation and killing
.
However, in the CTL eliminated by USP30 and the CTL treated with doxycycline, the expression of metabolic enzymes that can double as RNA-binding protein (RBP) has changed
.
Therefore, these findings indicate that the post-transcriptional regulation of RBP, a phenomenon well described in CTL, may regulate the selective down-regulation of protein synthesis detected after the loss of USP30
.

In summary, this study emphasizes the role of mitochondria as homeostasis regulators of CTL killing.
The translation of mitochondrial proteins keeps pace with the production of new cytolytic proteins
.
In this way, the energy requirements for protein synthesis can be fine-tuned to meet the continuous CTL killing requirements during the immune challenge
.

In summary, this study emphasizes the role of mitochondria as homeostasis regulators of CTL killing.
The translation of mitochondrial proteins keeps pace with the production of new cytolytic proteins
.
In this way, the energy requirements for protein synthesis can be fine-tuned to meet the continuous CTL killing requirements during the immune challenge
.
In summary, this study emphasizes the role of mitochondria as homeostasis regulators of CTL killing.
The translation of mitochondrial proteins keeps pace with the production of new cytolytic proteins
.
In this way, the energy requirements for protein synthesis can be fine-tuned to meet the continuous CTL killing requirements during the immune challenge
.

Reference:
Miriam Lisci et al.

Mitochondrial translation is required for sustained killing by cytotoxic T cells.

Reference:
Miriam Lisci et al.
Mitochondrial translation is required for sustained killing by cytotoxic T cells.
Science, 2021, doi:10.
1126/science.
abe9977.



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