title: Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus.
abstract: A diverse T cell repertoire is essential for a vigorous immune response to new infections, and decreasing repertoire diversity has been implicated in the age-associated decline in CD8 T cell immunity. In this study, using the well-characterized mouse influenza virus model, we show that although comparable numbers of CD8 T cells are elicited in the lung and lung airways of young and aged mice after de novo infection, a majority of aged mice exhibit profound shifts in epitope immunodominance and restricted diversity in the TCR repertoire of responding cells. A preferential decline in reactivity to viral epitopes with a low naive precursor frequency was observed, in some cases leading to "holes" in the T cell repertoire. These effects were also seen in young thymectomized mice, consistent with the role of the thymus in maintaining naive repertoire diversity. Furthermore, a decline in repertoire diversity generally correlated with impaired responses to heterosubtypic challenge. This study formally demonstrates in a mouse infection model that naturally occurring contraction of the naive T cell repertoire can result in impaired CD8 T cell responses to known immunodominant epitopes and decline in heterosubtypic immunity. These observations have important implications for the design of vaccine strategies for the elderly.
authors.affiliation: The Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Yager
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lanzer
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: David L
authors.initials: DL
authors.lastname: Woodland
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blackman
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D000940:Antigenic Variation; D000956:Antigens, Viral; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D019674:Genes, T-Cell Receptor beta; D007108:Immune Tolerance; D016056:Immunodominant Epitopes / Q000235:genetics; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013934:Thymectomy; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D016056:Immunodominant Epitopes; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; C061290:PA protein, influenza viruses; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014758:Viral Core Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase