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: Eric J Yager, Mushtaq Ahmed, Kathleen Lanzer, Troy D Randall, David L Woodland, Marcia A Blackman
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 205 Issue 3 Pg. 711-23 (Mar 17 2008) ISSN: 1540-9538 [Electronic] United States
• PMID: 18332179 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, immunology, pathogenicity)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Models, Immunological
• Nucleocapsid Proteins
• Nucleoproteins (genetics, immunology)
• Precursor Cells, T-Lymphoid (immunology)
• RNA-Binding Proteins (genetics, immunology)
• RNA-Dependent RNA Polymerase (genetics, immunology)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, metabolism)
• T-Lymphocytes (immunology)
• Thymectomy
• Viral Core Proteins (genetics, immunology)
• Viral Proteins (genetics, immunology)