Bordetella pertussis Induces Interferon Gamma Production by Natural Killer Cells, Resulting in Chemoattraction by Respiratory Epithelial Cells

Background. Whooping cough is caused by infection of the airways with Bordetella pertussis (Bp). As interferon gamma (IFN-gamma) is essential for protective immunity against Bp, we investigated how IFN-gamma is induced by Bp or the virulence antigens filamentous hemagglutinin adhesin, pertactin, or pertussis toxin, and how IFN-gamma contributes to local immune responses in humans. Methods. Peripheral blood mononuclear cells (PBMCs) from healthy donors and/or respiratory epithelial cells were stimulated with soluble antigens or inactivated intact Bp and the presence or absence of blocking antibodies or chemokines. Supernatants and cells were analyzed for IFN-gamma and chemokine production, and lymphocyte migration was tested using epithelial supernatants. Results. The soluble antigens failed to induce IFN-gamma production, whereas inactivated Bp induced IFN-gamma production. Natural killer (NK) cells were the main source of IFN-gamma production, which was enhanced by interleukin 15. Epithelial-PBMC co-cultures showed robust IFN-gamma-dependent CXCL9 and CXCL 10 production by the epithelial cells following stimulation with IFN-gamma and Bp. The epithelial-derived chemokines resulted in CXCR3-dependent recruitment of NK and T cells. Conclusions. Inactivated Bp, but not antigens, induced potent IFN-gamma production by NK cells, resulting in chemoattraction of lymphocytes toward the respiratory epithelium. These data provide insight into the requirements for IFN-gamma production and how IFN-gamma enhances local immune responses to prevent Bp-mediated disease.