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Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated

Ping Zhang1,2, Patrick MacLean3, Alicia Jia3

  • 1Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ping.zhang@well.ox.ac.uk.

Nature Communications
|February 25, 2026
PubMed

Insights

Genetic variants influence the mTOR pathway, impacting immune cell communication in sepsis. Specific genetic variations can improve sepsis survival by modulating T cell and neutrophil activity, offering a basis for personalized treatment strategies.

Area of Science:

  • Immunology
  • Genetics
  • Metabolism

Background:

  • Sepsis is a life-threatening condition with high mortality, necessitating personalized treatment approaches.
  • The mechanistic target of rapamycin (MTOR) pathway is crucial for regulating metabolism and immune responses during sepsis.
  • Genetic variations can influence MTOR activity and immune cell function in sepsis.

Purpose of the Study:

  • To characterize genetic variations modulating MTOR in sepsis.
  • To investigate the role of a specific variant (rs4845987) in MTOR expression and sepsis outcomes.
  • To elucidate the interaction between genetic factors, immune cell communication, and sepsis endotypes.

Main Methods:

  • Analysis of genetic variation associated with MTOR.
  • Ex vivo modeling of immune cell interactions (T cells and neutrophils).
  • Assessment of MTOR expression in immune cells under various conditions (hypoxia, rapamycin, vitamin C).

Main Results:

  • A specific genetic variant (rs4845987, G-allele) reduces MTOR expression in T cells, correlating with improved survival in pneumonia-induced sepsis.
  • The variant's effect on MTOR expression is context-specific, with opposing effects in T cells and neutrophils.
  • Activated T cells promote immunosuppressive neutrophils via cytokines, a process modulated by hypoxia, rapamycin, and vitamin C, influenced by the genetic variant.

Conclusions:

  • Genetic variation fine-tunes MTOR transcription and T cell activity through an epigenetic mechanism.
  • Immune cell communication in sepsis is modulated by genetic variation and disease state.
  • Findings provide a framework for stratified therapeutic interventions in sepsis based on genetic profiles.

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