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.
Highlights
In the waging battles between host immunity and microbial invaders, polymorphonuclear cells (PMN) or neutrophils are the most numerous cellular soldiers under the host banner
Several patient populations including those with cancer or that receive organ-transplants are at risk of life-threatening invasive fungal infections, in part due to reduced function or numbers of white blood cells
We describe a role for a poorly understood neutrophil called the neutrophil-dendritic cell hybrid (PMN-dendritic cells (DCs)) in antifungal immunity
Summary
In the waging battles between host immunity and microbial invaders, polymorphonuclear cells (PMN) or neutrophils are the most numerous cellular soldiers under the host banner. As the infantry of an inflammatory immune response, neutrophils are often the first leukocytes to infiltrate infected tissue armed with an arsenal of antimicrobial agents and functions for direct combat against intruders [1]. Defined, neutrophils are terminally differentiated and short-lived at sites of infection; there is a growing appreciation of long-lived neutrophils often accompanied by morphological changes [2]. One of these long-lived neutrophil populations has the morphology of dendritic cells (DCs) and can present antigen to T cells [3].
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