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T-Bet Expression Mediated by the mTOR Pathway Influences CD4+ T Cell Count in Mice With Lethal Candida Sepsis
Guangxu Bai1, Hao Wang1, Wen Han1
1Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Abstract:
The sustained high morbidity and mortality of Candida sepsis are mainly caused by compromise of host immunity. Clinically, it is often manifested as a significant decrease in CD4+ T cell count, although the mechanism is unclear. We established a lethal mice Candida sepsis model and used Murine Sepsis Score to group mice with different disease severity to establish the influence of T-bet expression on CD4+ T cell count in Candida sepsis. We found that CD4+ T cell count decreased in Candida-infected compared to uninfected mice, and the degree of decrease increased with aggravation of sepsis. Expression of T-bet similarly decreased with worsening of sepsis, but it was significantly enhanced in candidiasis in comparison of naïve state. To clarify its possible mechanism, we measured the activity of mammalian target of rapamycin (mTOR), which is a key regulator of T-bet expression. The mTOR pathway was activated after infection and its activity increased with progression of sepsis. We used mice with T-cell-specific knockout of mTOR or tuberous sclerosis complex (TSC)1 to further inhibit or strengthen the mTOR signaling pathway. We found that mTOR deletion mice had a higher CD4+ T cell count by regulating T-bet expression, and the result in TSC1 deletion mice was reversed. These results demonstrate that T-bet expression mediated by the mTOR pathway influences the CD4+ T cell count in mice with Candida sepsis.
Insights
In Candida sepsis, CD4+ T cell counts decrease due to compromised immunity. The mTOR pathway regulates T-bet expression, influencing CD4+ T cell levels during this infection.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Candida sepsis causes high morbidity and mortality, often linked to immune compromise and decreased CD4+ T cell counts.
- The precise mechanisms underlying CD4+ T cell depletion in Candida sepsis remain unclear.
Purpose of the Study:
- To investigate the role of T-bet expression in CD4+ T cell count changes during Candida sepsis.
- To elucidate the involvement of the mammalian target of rapamycin (mTOR) pathway in regulating T-bet expression and CD4+ T cell counts.
Main Methods:
- Established a lethal mouse model of Candida sepsis, categorizing severity using Murine Sepsis Score.
- Assessed CD4+ T cell counts and T-bet expression in relation to sepsis severity.
- Measured mammalian target of rapamycin (mTOR) pathway activity.
- Utilized T-cell-specific knockout mice for mTOR and tuberous sclerosis complex (TSC)1 to manipulate mTOR signaling.
Main Results:
- CD4+ T cell counts decreased with increasing Candida sepsis severity.
- T-bet expression decreased with sepsis severity but was enhanced in candidiasis compared to the naive state.
- mTOR pathway activation increased with sepsis progression.
- mTOR deletion in T cells increased CD4+ T cell counts, while TSC1 deletion reversed this effect, highlighting mTOR's role.
Conclusions:
- T-bet expression, modulated by the mTOR pathway, significantly influences CD4+ T cell counts in the context of Candida sepsis.
- Targeting the mTOR pathway may offer a therapeutic strategy to restore CD4+ T cell levels in Candida sepsis.
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