title: Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice.
abstract: In advanced age, decreased CD8(+) cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8(+) T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8(+) T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8(+) T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8(+) T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8(+) T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging.
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Quinn
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Sophie G
authors.initials: SG
authors.lastname: Zaloumis
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Tania
authors.initials: T
authors.lastname: Cukalac
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Kan
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Xavier Y X
authors.initials: XY
authors.lastname: Sng
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Michiko
authors.initials: M
authors.lastname: Mirams
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Watson
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3000, Australia; School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3000, Australia; Modelling and Simulation, Infection and Immunity Theme, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia;
authors.forename: James M
authors.identifier: http://orcid.org/0000-0002-2452-3098
authors.initials: JM
authors.lastname: McCaw
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; pcd@unimelb.edu.au nllg@unimelb.edu.au.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, GA 30602.
authors.forename: Andreas
authors.initials: A
authors.lastname: Handel
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au nllg@unimelb.edu.au.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: CD44+ virtual memory; CD5; aging; influenza A virus; naive CD8+ T cells