Immunological Signatures of Sepsis in Solid Organ Transplant Recipients: A Multilayer and Multicentric Prospective Cohort Study

Background : Sepsis is characterized by a dysregulated host response. Patients with prior solid organ transplantation (SOT) are highly susceptible to infection due to chronic immunosuppression, yet exhibit improved survival once sepsis occurs. The underlying mechanisms remain poorly understood. Methods : We analyzed a prospective multicenter cohort of septic intensive care unit patients (SepsisDataNet.NRW; n=538). Clinical outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression. Immune profiling included serum cytokines, flow cytometric immunophenotyping, plasma proteomics, and intracellular signaling using proximity ligation assays (PLA) in peripheral blood mononuclear cells (PBMCs). To reduce clinical confounding, ex vivo lipopolysaccharide (LPS) stimulation experiments were performed in PBMCs of a non-septic kidney transplantation cohort (e:kid; n=10) obtained before and after organ-transplantation. Results : SOT patients demonstrated improved 30-day survival compared with non-SOT patients (84% vs. 66%; adjusted HR 0.49, 95% CI 0.26-0.95). Cytokine analysis revealed reduced IL-6 and TNF-α levels, alongside increased IL-18, indicating attenuation of hyperinflammation with preserved innate activation. Flow cytometry showed reductions in adaptive immune cells but relatively preserved innate immune function, reflected by higher monocytic HLA-DR expression. Proteomics identified enrichment of innate immune, complement, lipid metabolic response networks. At cellular level, SOT patients exhibited increased GLUT1 expression and enhanced TFAM/TFB2M interaction, indicating coordinated immunometabolism. Conclusion : Septic SOT patients display a reprogrammed immune response characterized by attenuation of hyperinflammation, preservation of innate immune competence, and coordinated immunometabolism. This immune pattern may underlie the observed survival advantage and provides a mechanistic framework for targeted therapeutic strategies in sepsis. Take Home Message: Septic patients with prior solid organ transplantation show improved 30-day survival despite chronic immunosuppression. This study provides the first comprehensive multilayer characterization of their immune response, demonstrating a reprogrammed profile with attenuated systemic inflammation, relative preservation of innate immune competence, and coordinated immunometabolism. These findings challenge the concept of global immunosuppression and suggest that distinct host-response patterns may contribute to outcome differences in sepsis.