Investigation of the compartmentalized immune response in acute sepsis reveals a liver exclusive T cell mediated cytotoxicity indispensable for survival 9189

Abstract Description The spatiotemporal regulation of immune response during polymicrobial sepsis needs further investigation. We use a refined Peritoneal Contamination and Infection model mimicking the clinics and perform targeted secretome profiling, immunophenotyping and machine learning across 5 tissues (peritoneal cavity, liver, spleen, blood, BM) 6h post infection to address the contribution and prediction value of immune cells and factors to early sepsis. Based on the secreted mediators, we identify a shared sepsis signature, but each organ additionally harbors a unique secretory fingerprint. Our top predictors include IL-6 and the novel CXCL9 which outperform others like CRP. Supporting the organ self-regulation hypothesis we identified only scarce immune cell-cell correlations across organs in both healthy and septic mice. The innate cell infiltration reflects pathogen dissemination as neutrophils egress from BM to enter the peritoneum and liver, but not spleen. There we observe a unique B cell increase instead, while exclusively in liver a T cell infiltration mediated partially by CXCL9, further supporting unique tissue-orchestrated responses. scRNA-Seq showed that T cells in liver produce cytotoxic substances including TRAIL. To determine their role in vivo we inhibited the CXCL9-CXCR3 axis which lead to decreased survival, potentially due to increased pathogen load. To conclude, we report a highly compartmentalized immune response and a T cell toxicity in liver indispensable for sepsis. Funding Sources Collaborative Research Center PolyTarget SFB 1278 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)