CD200R^high neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T...

Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200R^high neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (T_reg) cells. Compared to their CD200R^low counterparts, sepsis-generated CD200R^high neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200R^high neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200R^high neutrophils expressed high levels of Igf1, which elicits the generation of T_reg cells, while the administration of an α-CD200R antibody inhibited T_reg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200R^high neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating T_reg cells.