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<p>Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates <i>MTOR</i>, a critical regulator of metabolism and immune responses in sepsis. The effects are context specific, involving a regulatory element that affects <i>MTOR</i> expression in activated T cells with opposite effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, which is associated with decreased risk of type 2 diabetes, reduces <i>MTOR</i> expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates an epigenetic mechanism fine-tuning <i>MTOR</i> transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a framework for stratified therapy in sepsis.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月25日

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  • Ping Zhang,
  • Patrick MacLean,
  • Alicia Jia,
  • Callum R. O’Neill,
  • Alice Allcock,
  • Ethan Prince,
  • Bora Ozcan,
  • Roman M. Doll,
  • Imogen Dyne,
  • Kiki Cano-Gamez,
  • Hanyu Qin,
  • Chloe Wainwright,
  • Giuseppe Scozzafava,
  • Andrew C. Brown,
  • James O. J. Davies,
  • Amanda Y. Chong,
  • Alexander J. Mentzer,
  • Katie L. Burnham,
  • Emma E. Davenport,
  • Julian C. Knight

摘要

Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates MTOR, a critical regulator of metabolism and immune responses in sepsis. The effects are context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, which is associated with decreased risk of type 2 diabetes, reduces MTOR expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates an epigenetic mechanism fine-tuning MTOR transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a framework for stratified therapy in sepsis.