Article
Distinct Aspergillus fumigatus morphotypes induce neutrophilic CXCR4high myeloid-derived suppressor cells through a Dectin-1-mediated mechanism
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Published: | March 28, 2013 |
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Introduction: The coordinated action of both innate and adaptive immunity is essential to protect the host against Aspergillus fumigatus. Innate myeloid cells recognize the fungus, while T cells orchestrate long-term immune responses. However, overreactive T cell responses drive hyperinflammation with enhanced tissue damage and defective fungal clearance. The mechanisms by which A. fumigatus modulates T cell reactivity are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in pro-inflammatory microenvironments and capable of suppressing T cell responses. We hypothesized that A. fumigatus induces MDSCs to modulate T cell immunity.
Material and Methods: MDSCs were characterized as CD33highCXCR4highHLA-DRinter neutrophilic cells after in vitro culture of healthy control PBMC with different A. fumigatus morphotypes and supernatants or dectin-1 ligands. The functionality of MACS-isolated MDSCs was assessed using T cell proliferation, NK cell cytotoxicity and cytokine / chemokine analysis.
Results: A. fumigatus hyphae or germ tubes, but not conidia, induced MDSCs in vitro. This effect was independent from infection and mediated through a shedded pathogen-associated molecular pattern, since both killed hyphae or germ tubes as well as cell-culture supernatants from the according morphotypes induced MDSCs. A. fumigatus-induced MDSCs were distinct from canonical GM-CSF-induced MDSCs, since they expressed CXCR4 and, to a lesser extent, HLA-DR on their surface. CXCR4high MDSCs were functionally competent, as they suppressed polyclonal T cell proliferation, Th1, Th2, Th17 and chemokine responses and dampened NK cell functionality. Since A. fumigatus cell walls contain a high β-glucan content and the MDSC-inducing effects of A. fumigatus-derived supernatants were independent from heat-inactivation, we studied the contribution of the β-glucan receptor dectin-1 in MDSC generation. Dectin-1 ligation mimicked the induction of the CXCR4high MDSC phenotype as seen by using A. fumigatus-derived supernatants, an effect that was largely abrogated by blocking dectin-1.
Conclusion: These studies demonstrate that distinct morphologies of A. fumigatus induce a specific subset of CXCR4high MDSCs through a dectin-1-mediated mechanism. The fungus may utilize this mechanism to dampen pro-inflammatory T and NK cell responses as reaction to growing A. fumigatus morphotypes and to establish a bistable host-pathogen interaction.