Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in sepsis, modulating disease

Sepsis is a heterogeneous clinical syndrome with a high mortality rate and personalised stratification strategies are proposed as essential to successful targeted therapeutics. Here, we characterise genetic variation that modulates MTOR , a critical regulator of metabolism and immune responses in sepsis. The effects are highly context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite direction of effect in neutrophils. The lead variant, rs4845987, significantly interacts with the known sepsis prognostic marker neutrophil-to-lymphocyte ratio, shows activity specific to sepsis endotype, and a pleiotropic effect on type 2 diabetes (T2D) risk. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive sepsis neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. The G-allele of rs4845987, associated with decreased risk of T2D, is associated with reduced mTOR signaling in T cells and improved survival in sepsis patients due to pneumonia. We define a novel epigenetic mechanism that fine-tunes MTOR transcription and T cell activity via the variant-containing regulatory element, which exhibits an allelic effect upon vitamin C treatment. Our findings reveal how common genetic variation can interact with disease state/endotype to modulate immune cell-cell communication, providing a patient stratification strategy to inform more effective treatment of sepsis.