title: Intrinsic 4-1BB signals are indispensable for the establishment of an influenza-specific tissue-resident memory CD8 T-cell population in the lung.
abstract: The induction of long-lived heterotypic T-cell protection against influenza virus remains elusive, despite the conservation of T-cell epitopes. T-cell protection against influenza is critically dependent on lung-resident memory T cells (Trm). Here we show that intranasal administration of 4-1BBL along with influenza nucleoprotein in a replication-defective adenovirus vector to influenza pre-immune mice induces a remarkably stable circulating effector memory CD8 T-cell population characterized by higher IL-7Rα expression than control-boosted T cells, as well as a substantial lung parenchymal CD69+CD8 Trm population, including both CD103+and CD103-cells. These T-cell responses persist to greater than 200 days post-boost and protect against lethal influenza challenge in aged (year old) mice. The expansion of the nucleoprotein-specific CD8 Trm population during boosting involves recruitment of circulating antigen-specific cells and is critically dependent on local rather than systemic administration of 4-1BBL as well as on 4-1BB on the CD8 T cells. Moreover, during primary influenza infection of mixed bone marrow chimeras, 4-1BB-deficient T cells fail to contribute to the lung-resident Trm population. These findings establish both endogenous and supraphysiological 4-1BBL as a critical regulator of lung-resident memory CD8 T cells during influenza infection.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A C
authors.initials: AC
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: L E
authors.initials: LE
authors.lastname: Wagar
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Wortzman
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D039001:Integrin alpha Chains / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology
chemical_list: D053330:4-1BB Ligand; D015703:Antigens, CD; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D007252:Influenza Vaccines; D039001:Integrin alpha Chains; D020395:Receptors, Interleukin-7; C091367:alpha E integrins; C415350:interleukin-7 receptor, alpha chain