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Published on: November 6, 2020
CD8+ T cell survival in lethal fungal sepsis was ameliorated by T-cell-specific mTOR deletion
1Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China.
Abstract:
Lethal fungal sepsis causes high morbidity and mortality in intensive care patients. Fungal infections have an immunological basis, and it has been shown in recent studies that decreased CD8+ T-cell count in fungal infections is related to prognosis, while the underlying mechanism is still unclear. Here, a lethal fungal sepsis model induced by candidemia was created and we found a decreased CD8+ T-cell count and exaggerated apoptosis. Simultaneously, expression of light chain (LC)3B in CD8+ T cells increased, along with increased autophagosomes and accumulation of p62 in infected mice. We regulated the activity of the mammalian target of rapamycin (mTOR) pathway using T-cell-specific mTOR/ TSC1 deletion mice. We observed increased number of autophagosomes and expression of LC3B in CD8+T cells after T-cell-specific mTOR knockout, while accumulation of p62 was not ameliorated, and there was no increase in the number of autolysosomes. Apoptosis rate and expression of BIM, a pro-apoptotic gene, decreased in CD8+ T cells in mTOR-deletion mice but increased in TSC1-deletion mice. Our results showed increased CD8+ T-cell death in spleen of lethal fungal sepsis mice, and decreased expression of mTOR ameliorated CD8+ T-cell survival. mTOR may be a possible target to reverse CD8+ T-cell immune dysfunction in lethal fungal sepsis.
Insights
In lethal fungal sepsis, CD8+ T-cell death increases. Targeting the mammalian target of rapamycin (mTOR) pathway may improve CD8+ T-cell survival and combat immune dysfunction in these critical patients.
Area of Science:
- Immunology
- Cell Biology
- Intensive Care Medicine
Background:
- Fungal sepsis leads to high mortality in intensive care units.
- Decreased CD8+ T-cell counts correlate with poor prognosis in fungal infections, but mechanisms are unclear.
- Autophagy and apoptosis pathways are implicated in T-cell dysfunction during sepsis.
Purpose of the Study:
- To investigate the role of the mammalian target of rapamycin (mTOR) pathway in CD8+ T-cell immune dysfunction during lethal fungal sepsis.
- To explore the impact of modulating mTOR activity on CD8+ T-cell survival and function.
- To identify potential therapeutic targets for reversing T-cell dysfunction in fungal sepsis.
Main Methods:
- Established a lethal fungal sepsis model using candidemia in mice.
- Utilized T-cell-specific mTOR/TSC1 deletion mouse models to investigate pathway regulation.
- Analyzed CD8+ T-cell apoptosis, autophagy markers (LC3B, p62, autophagosomes, autolysosomes), and pro-apoptotic gene expression (BIM).
Main Results:
- Lethal fungal sepsis induced decreased CD8+ T-cell counts, increased apoptosis, and altered autophagy markers (increased LC3B, p62 accumulation).
- T-cell-specific mTOR knockout increased autophagosomes and LC3B but did not resolve p62 accumulation or increase autolysosomes.
- mTOR deletion decreased CD8+ T-cell apoptosis and BIM expression, enhancing T-cell survival, while TSC1 deletion had opposite effects.
Conclusions:
- Decreased mTOR expression ameliorates CD8+ T-cell death and improves survival in a lethal fungal sepsis model.
- The mTOR pathway is a potential therapeutic target for restoring CD8+ T-cell immune function in severe fungal infections.
- Modulating mTOR activity offers a promising strategy to improve outcomes for intensive care patients with fungal sepsis.
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