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

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 highly context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite direction of effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, associated with decreased risk of T2D, reduces MTOR expression in T cells and improves survival in sepsis patients due to pneumonia, with effects specific to sepsis endotype. 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. Our work demonstrates 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. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a patient stratification strategy to inform more effective sepsis treatment. Contents This submission contains processed ATAC-seq and RNA-seq results, including raw and normalised counts along with bigWig files for genome-wide signal data from human primary CD4+ and CD8+ T cells with (Day-4) and without (Day-0) anti-CD3/CD28 Dynabead stimulation, derived from three healthy donors. The corresponding raw FASTQ files can be accessed at the European Genome-phenome Archive (EGA) under accession number EGAS50000000894 (https://ega-archive.org/studies/EGAS50000000894). All code used for data processing and analysis in this study is publicly available on GitHub (https://github.com/jknightlab/MTOR-Genetics-Project).