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

Journal article

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.

Authors: Zhang, P; MacLean, P; Jia, A; O’Neill, CR; Allcock, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 3201
• Publication date: 2026-02-25
• Acceptance date: 2026-02-11
• DOI: 10.1038/s41467-026-69919-7
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: PI3K/AKT/mTOR pathway; Sepsis; Immune system; Regulator; Epigenetics; Ex vivo; Context (archaeology); Genetic variation; Mechanistic target of rapamycin