Abstract
Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response.
Highlights
natural killer (NK) cells comprise 5–15% of the peripheral blood mononuclear cells (PBMCs) in healthy individuals and belong to the innate immune system[5]
NKp30 has been described as a pathogen recognition receptors (PRRs) for fungal pathogens[8, 24], no significant changes were detected in the presence of A. fumigatus (Supplementary Fig. 1)
This study is the first to visualize the direct interaction of NK cells and A. fumigatus and to show that CD56 has a functional role during fungal recognition
Summary
NK cells comprise 5–15% of the peripheral blood mononuclear cells (PBMCs) in healthy individuals and belong to the innate immune system[5]. NK cells release immune regulatory cytokines to stimulate other immune cells and display cytotoxicity directed against tumor or virus-infected cells by granule release[5]. The function of NK cells is induced by the interplay of inhibitory and activating receptors[7], leading to cytotoxicity directed against tumors and virus-infected cells. Previous studies demonstrated that NK cells are activated by direct interaction with A. fumigatus germ tubes and hyphae[11, 14]. Direct contact with A. fumigatus germ tubes induces IFNγ release of NK cells which interferes with fungal metabolic activity and growth[11]. Studies in a neutropenic IA mouse model demonstrated that NK cell recruitment is essential for the clearance of the fungal infection and that IFNγ release by NK cells is critical for the immune defense during IA17, 18. We showed that blocking of CD56 reduced NK cell activation and partially restored CD56 fluorescence positivity of NK cells suggesting that CD56 is one recognition receptor for A. fumigatus
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