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

Abstract

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 proportion of Gr-1^hi cells and a decrease in the proportion of T cells on day 7; levels of these cells eventually return to levels similar to those of control mice on day 21. T-cell activation and gamma interferon (IFN-γ) expression by CD8⁺ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1^hi cells showed a CD11b⁺ Ly6G^hi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired interleukin 6 (IL-6) production in serum, accompanied by accumulation of CD11b⁺ Gr-1^hi cells in the peripheral blood. Transfer of Gr-1^hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1^hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1^hi 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-1^hi cells in the early phase of sepsis is required for the late phase of immune paralysis.

Keywords: immune checkpoint; myeloid cells; sepsis.