Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells

• Published in: The Journal of infectious diseases 2017-12, Vol.216 (10), p.1281-1294
• Main Authors: Stephen-Victor, Emmanuel, Karnam, Anupama, Fontaine, Thierry, Beauvais, Anne, Das, Mrinmoy, Hegde, Pushpa, Prakhar, Praveen, Holla, Sahana, Balaji, Kithiganahalli N., Kaveri, Srini V., Latgé, Jean-Paul, Aimanianda, Vishukumar, Bayry, Jagadeesh
• Format: Article
• Language: English
• Subjects: Allergology; Animals; Aspergillus fumigatus - immunology; B7-H1 Antigen - genetics; Biomarkers; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; FUNGI; Gene Expression; Glucans - immunology; Humans; Immunology; Innate immunity; Interferon-gamma - metabolism; Life Sciences; Lymphocyte Activation - immunology; Mice; Mice, Knockout; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jix469

α-(1,3)-Glucan polysaccharide of Aspergillus fumigatus induces human dendritic cell maturation and stimulates regulatory T-cell (Treg) responses by the PD-L1-dependent pathway. PD-L1 inhibition significantly enhanced α-(1,3)-glucan-mediated IFN-γ secretion, indicating that the PD-1–PD-L1 pathway could be targeted to enhance protective immune responses to A. fumigatus infections. Abstract Background Human dendritic cell (DC) response to α-(1,3)-glucan polysaccharide of Aspergillus fumigatus and ensuing CD4+ T-cell polarization are poorly characterized. Methods α-(1,3)-Glucan was isolated from A. fumigatus conidia and mycelia cell wall. For the analysis of polarization, DCs and autologous naive CD4+ T cells were cocultured. Phenotype of immune cells was analyzed by flow cytometry, and cytokines by enzyme-linked immunosorbent assay (ELISA). Blocking antibodies were used to dissect the role of Toll-like receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) in regulating α-(1,3)-glucan-mediated DC activation and T-cell responses. DCs from TLR2-deficient mice were additionally used to consolidate the findings. Results α-(1,3)-Glucan induced the maturation of DCs and was dependent in part on TLR2. “α-(1,3)-Glucan-educated” DCs stimulated the activation of naive T cells and polarized a subset of these cells into CD4+CD25+FoxP3+ regulatory T cells (Tregs). Mechanistically, Treg stimulation by α-(1,3)-glucan was dependent on the PD-L1 pathway that negatively regulated interferon-gamma (IFN-γ) secretion. Short α-(1,3)-oligosaccharides lacked the capacity to induce maturation of DCs but significantly blocked α-(1,3)-glucan-induced Treg polarization. Conclusions PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1–PD-L1 to enhance protective immune responses to A. fumigatus infections.