Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus

J Exp Med. 2008 Mar 17;205(3):711-23. doi: 10.1084/jem.20071140. Epub 2008 Mar 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology*
  • Animals
  • Antigenic Variation
  • Antigens, Viral
  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • Genes, T-Cell Receptor beta
  • Immune Tolerance
  • Immunodominant Epitopes / genetics
  • Influenza A virus / genetics
  • Influenza A virus / immunology*
  • Influenza A virus / pathogenicity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Models, Immunological
  • Nucleocapsid Proteins
  • Nucleoproteins / genetics
  • Nucleoproteins / immunology
  • Precursor Cells, T-Lymphoid / immunology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Lymphocytes / immunology*
  • Thymectomy
  • Viral Core Proteins / genetics
  • Viral Core Proteins / immunology
  • Viral Proteins / genetics
  • Viral Proteins / immunology

Substances

  • Antigens, Viral
  • Immunodominant Epitopes
  • NP protein, Influenza A virus
  • Nucleocapsid Proteins
  • Nucleoproteins
  • PA protein, influenza viruses
  • RNA-Binding Proteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Viral Core Proteins
  • Viral Proteins
  • influenza virus polymerase basic protein 1
  • RNA-Dependent RNA Polymerase