Sepsis impairs immunocompetent plasmacytoid dendritic cell reconstitution from hematopoietic stem/progenitor cell through altered bone marrow environment

Abstract

Plasmacytoid dendritic cells (pDCs) are crucial components of the immune response during viral infections, yet their function and development in the late phase of sepsis remain poorly understood. In this study, we investigated the impact of prolonged sepsis on pDCs and their progenitors in cecal ligation and puncture (CLP)-induced septic mice. We observed a significant reduction in both pDCs and their progenitors, alongside the presence of mature and regulatory pDCs. These mature and regulatory pDCs exhibited impaired type I interferon (IFN) secretion and antigen presentation capacity. In a Flt3L culture system of hematopoietic stem/progenitor cells (HSPCs) from CLP and Sham mice, we found that CLP-derived HSPCs exhibited an impaired ability to generate immunocompetent pDCs, as evidenced by lower IFN-α expression and reduced pDC recovery. Further investigation revealed downregulation of the key transcription factor TCF4 during pDC differentiation in these progenitor cells. Ectopic expression of TCF4 in these progenitors restored pDC generation. Additionally, we observed elevated levels of granulocyte colony-stimulating factor (G-CSF) in the bone marrow supernatant of septic mice. The addition of G-CSF to the culture system significantly impaired the generation of immunocompetent pDCs from HSPCs of normal mice. These findings suggest that sepsis may impair the production of immunocompetent pDCs from HSPCs by modulating key genes involved in pDC differentiation, potentially contributing to immune suppression and increased susceptibility to opportunistic infections in the later stages of sepsis.