title: Respiratory macrophages regulate CD4 T memory responses to mucosal immunization with recombinant adenovirus-based vaccines.
abstract: Respiratory immunization is an attractive way to generate systemic and mucosal protective memory responses that are required for preventing mucosally transmitted infections. However, the molecular and cellular mechanisms for controlling memory T cell responses remain incompletely understood. In this study, we investigated the role of respiratory macrophage (MΦ) in regulating CD4 T cell responses to recombinant adenovirus-based (rAd) vaccines. We demonstrated that rAd intranasal (i.n.) vaccination induced migration and accumulation of respiratory MΦ and circulatory monocytes in the mediastinal lymph nodes and lung parenchyma. Under the influence of respiratory MΦ CD4 T cells exhibited slow proliferation kinetics and an increased tendency of generating central memory, as opposed to effector memory, CD4 T cell responses in vitro and in vivo. Correspondingly, depletion of MΦ using clodronate-containing liposome prior to i.n. immunization significantly enhanced CD4 T cell proliferation and increased the frequency of CD4 memory T cells in the airway lumen, demonstrating that MΦ initially serve as a negative regulator in limiting generation of mucosal tissue-resident memory CD4 T cells. However, clodronate-containing liposome delivery following i.n. immunization markedly reduced the frequencies of memory CD4 T cells in the airway lumen and spleen, indicating that respiratory MΦ and potentially circulating monocytes are critically required for maintaining long-term memory CD4 T cells. Collectively, our data demonstrate that rAd-induced mucosal CD4 T memory responses are regulated by respiratory MΦ and/or monocytes at multiple stages.
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Acosta-Ramirez
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tram
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Kampen
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Tillman
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Pediatrics, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Halperin
authors.affiliation: Canadian Center for Vaccinology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Pediatrics, Faculty of Medicine, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, Canada. Electronic address: jun.wang@dal.ca.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000008:administration & dosage; D005260:Female; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D014614:Vaccines, Synthetic; D004002:Clodronic Acid
keywords: Adenovirus-based vaccine; CD4 T cells; Intranasal immunization; Memory response; Respiratory macrophages