Journal
FRONTIERS IN IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.03034
Keywords
regulatory B cells; CD9(+) B cells; severe asthma; apoptosis; effector T cells
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Funding
- l'Institut de Recherche en Sante Respiratoire-Pays de la Loire
- Region Pays de la Loire
- IHU-Cesti project
- DHU Oncogreffe
- French government [ANR-10-IBHU-005, ANR-11-LABX-0016-01]
- Nantes Metropole
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CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9(+) IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9(+) B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9(+) B cells in human and mouse. The profile of CD9(+) B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9(+) B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19(+)CD9(+) B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9(+) B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9(+) B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9(+) B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients.
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