title: Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease.
abstract: A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. Transfer of T cells lacking the proapoptotic molecule Bim extends the lifespan of 4-1BBL-deficient mice by one to three days, suggesting that at least part of the role of 4-1BB/4-1BBL is to prolong effector cell survival long enough to clear virus. Intranasal delivery of 4-1BBL by recombinant adenovirus marginally improves survival of 4-1BBL-deficient mice at low dose, but exacerbates disease at high dose. These findings suggest a rationale for the evolutionary accumulation of inducible costimulatory molecules, thereby allowing the immune system to sustain the expression of molecules such as 4-1BB to a level commensurate with severity of infection.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Sedgmen
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Moraes
authors.forename: Laura M
authors.initials: LM
authors.lastname: Snell
authors.forename: David J
authors.initials: DJ
authors.lastname: Topham
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000281:Administration, Intranasal; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016056:Immunodominant Epitopes / Q000032:analysis / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D011024:Pneumonia, Viral / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014774:Virulence
chemical_list: D053330:4-1BB Ligand; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9