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

Abstract 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.