title: Mechanisms of mucosal and parenteral tuberculosis vaccinations: adenoviral-based mucosal immunization preferentially elicits sustained accumulation of immune protective CD4 and CD8 T cells within the airway lumen.
abstract: The mechanisms underlying better immune protection by mucosal vaccination have remained poorly understood. In our current study we have investigated the mechanisms by which respiratory virus-mediated mucosal vaccination provides remarkably better immune protection against pulmonary tuberculosis than parenteral vaccination. A recombinant adenovirus-based tuberculosis (TB) vaccine expressing Mycobacterium tuberculosis Ag85A (AdAg85A) was administered either intranasally (i.n.) or i.m. to mice, and Ag-specific CD4 and CD8 T cell responses, including frequency, IFN-gamma production, and CTL, were examined in the spleen, lung interstitium, and airway lumen. Although i.m. immunization with AdAg85A led to activation of T cells, particularly CD8 T cells, in the spleen and, to a lesser extent, in the lung interstitium, it failed to elicit any T cell response in the airway lumen. In contrast, although i.n. immunization failed to effectively activate T cells in the spleen, it uniquely elicited higher numbers of Ag-specific CD4 and CD8 T cells in the airway lumen that were capable of IFN-gamma production and cytolytic activities, as assessed by an intratracheal in vivo CTL assay. These airway luminal T cells of i.n. immunized mice or splenic T cells of i.m. immunized mice, upon transfer locally to the lungs of naive SCID mice, conferred immune protection against M. tuberculosis challenge. Our study has demonstrated that the airway luminal T cell population plays an important role in immune protection against pulmonary TB, thus providing mechanistic insights into the superior immune protection conferred by respiratory mucosal TB vaccination.
authors.affiliation: Department of Pathology and Molecular Medicine and Division of Infectious Diseases, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Xizhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Hitt
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000217:Acyltransferases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001980:Bronchi / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D007117:Immunization, Secondary; D007273:Injections, Intramuscular; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D032581:Tuberculosis Vaccines; D014614:Vaccines, Synthetic; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis