An Unappreciated Role for neutrophil-DC Hybrids in Immunity to Invasive Fungal Infections

PLoS Pathog. 2018 May 21;14(5):e1007073. doi: 10.1371/journal.ppat.1007073. eCollection 2018 May.

Abstract

Neutrophils are classically defined as terminally differentiated, short-lived cells; however, neutrophils can be long-lived with phenotypic plasticity. During inflammation, a subset of neutrophils transdifferentiate into a population called neutrophil-DC hybrids (PMN-DCs) having properties of both neutrophils and dendritic cells. While these cells ubiquitously appear during inflammation, the role of PMN-DCs in disease remains poorly understood. We observed the differentiation of PMN-DCs in pre-clinical murine models of fungal infection: blastomycosis, aspergillosis and candidiasis. Using reporter strains of fungal viability, we found that PMN-DCs associate with fungal cells and kill them more efficiently than undifferentiated canonical neutrophils. During pulmonary blastomycosis, PMN-DCs comprised less than 1% of leukocytes yet contributed up to 15% of the fungal killing. PMN-DCs displayed higher expression of pattern recognition receptors, greater phagocytosis, and heightened production of reactive oxygen species compared to canonical neutrophils. PMN-DCs also displayed prominent NETosis. To further study PMN-DC function, we exploited a granulocyte/macrophage progenitor (GMP) cell line, generated PMN-DCs to over 90% purity, and used them for adoptive transfer and antigen presentation studies. Adoptively transferred PMN-DCs from the GMP line enhanced protection against systemic infection in vivo. PMN-DCs pulsed with antigen activated fungal calnexin-specific transgenic T cells in vitro and in vivo, promoting the production of interferon-γ and interleukin-17 in these CD4+ T cells. Through direct fungal killing and induction of adaptive immunity, PMN-DCs are potent effectors of antifungal immunity and thereby represent innovative cell therapeutic targets in treating life-threatening fungal infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen Presentation
  • Aspergillus fumigatus / immunology
  • Blastomyces / immunology
  • Blastomycosis / immunology*
  • Bone Marrow Cells / immunology
  • Candida albicans / immunology
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Hybrid Cells / immunology*
  • Invasive Fungal Infections / immunology*
  • Kidney / microbiology
  • Kidney / pathology
  • Lung / microbiology
  • Lung / pathology
  • Lung Diseases, Fungal / immunology
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Scanning
  • Neutrophils / immunology*
  • Nitrous Oxide / analysis
  • Reactive Oxygen Species / analysis
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / microbiology

Substances

  • Reactive Oxygen Species
  • Nitrous Oxide