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Updated: Sep 26, 2025
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
mTOR deletion ameliorates CD4 + T cell apoptosis during sepsis by improving autophagosome-lysosome fusion
Hao Wang1, Guangxu Bai2, Jianwei Chen2
1Department of Critical Care Medicine, Beijing Jishuitan Hospital, 100035, Beijing, China.
Abstract:
Autophagy dysfunction contributes to CD4 + T cell apoptosis during sepsis leading to impairment of adaptive immunity. However, the underlying mechanism is unclear. The mammalian target of rapamycin (mTOR) pathway modulates CD4 + T cell survival during sepsis through mechanisms that are not fully understood. We developed a mouse model of sepsis through cecal ligation and puncture (CLP) to investigate dynamic changes in autophagy in CD4 + T cells. We used T cell specific-mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice to explore the roles of the mTOR pathway in modulating autophagy during sepsis. We observed reduced fusion of autophagosomes with lysosomes in the CD4 + T cells of CLP mice, which may represent a characteristic feature of autophagy dysfunction. Deletion of mTOR relieved autophagosome-lysosome fusion dysfunction and ameliorated apoptosis of CD4 + T cells in CLP mice, but this rescued phenotype was abolished by treatment with bafilomycin A1, a specific A-L fusion inhibitor. We further explored the underlying molecular mechanism and found that phosphorylation levels of transcription factor EB were significant higher in CLP mice and that expression of A-L fusion protein SNAREs were restricted, both of which were ameliorated by mTOR deletion. Taken together, these results suggest that the mTOR pathway plays a critical role in regulation of CD4 + T-cell apoptosis during sepsis, partly through regulation of A-L fusion-related protein transcription.
Insights
Sepsis impairs adaptive immunity by causing CD4+ T cell apoptosis due to autophagy dysfunction. Targeting the mTOR pathway can restore autophagosome-lysosome fusion, reducing T cell death during sepsis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Autophagy dysfunction in CD4+ T cells contributes to apoptosis and impaired adaptive immunity during sepsis.
- The precise mechanisms by which the mammalian target of rapamycin (mTOR) pathway influences CD4+ T cell survival in sepsis remain incompletely understood.
Purpose of the Study:
- To investigate the dynamic changes in autophagy within CD4+ T cells during sepsis.
- To elucidate the role of the mTOR pathway in modulating autophagy and CD4+ T cell apoptosis in a mouse model of sepsis.
Main Methods:
- A mouse model of sepsis was established using cecal ligation and puncture (CLP).
- T cell-specific mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice were utilized to study mTOR pathway function.
- Autophagosome-lysosome fusion, CD4+ T cell apoptosis, and related molecular mechanisms (transcription factor EB, SNAREs) were analyzed.
Main Results:
- Sepsis induced reduced autophagosome-lysosome fusion in CD4+ T cells, a hallmark of autophagy dysfunction.
- mTOR deletion ameliorated this fusion defect and reduced CD4+ T cell apoptosis in septic mice.
- mTOR deletion normalized elevated phosphorylation of transcription factor EB and restored expression of autophagosome-lysosome fusion-related SNARE proteins.
Conclusions:
- The mTOR pathway is critical in regulating CD4+ T cell apoptosis during sepsis.
- mTOR regulates this process, at least partly, by controlling the transcription of proteins involved in autophagosome-lysosome fusion.
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