Polymorphonuclear Myeloid-Derived Cells that Contribute to the Immune Paralysis Are Generated in the Early Phase of Sepsis via the PD-1/PD-L1 Pathway

Immune paralysis is a protracted state of immune suppression following the early/acute inflammatory phase of sepsis. CD11b+Gr-1+ cells induced during sepsis are heterogeneous myeloid-derived cells (MDCs). This study investigated the contribution of MDCs to immune paralysis. Treatment of mice with zymosan (ZM) induced a marked increase in the total number of splenocytes with an increase in the ratio of Gr-1hi cells and a decease in the ratio of T cells on day 7, eventually returning to levels similar to those of control mice on day 21. T cell activation and IFN-γ expression by CD8+ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1hi cells showed a CD11b+Ly6Ghi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired IL-6 production in serum, accompanied by accumulation of CD11b+Gr-1hi cells in the peripheral blood. Transfer of Gr-1hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1hi cells by treatment with anti-Gr-1 monoclonal antibody (mAb) or neutralization of the PD-1/PD-L1 pathway by anti-PD-1 and anti-PD-L1 mAbs during the induction phase of sepsis ameliorated ZM-induced immune suppression. Our results suggest that the PD-1/PD-L1-mediated generation of Gr-1hi cells in the early phase of sepsis is required for late-phase of immune paralysis.