Narrowing of human influenza A virus-specific T cell receptor α and β repertoires with increasing age
Open accessAbstract
Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV Vα and Vβ T cell repertoires specific to M1 residues 58 to 66 (M1 58–66 ), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The Vα repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced cross-reactivity. IMPORTANCE With increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M1 58–66 peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination.
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Human CD8+ T cell responses against the HLA-A2-restricted M158-66 influenza A peptide narrow with age, possibly impairing recognition of antigenically related viruses.
“human CD8+ T cell responses directed against the HLA-A2-restricted M158-66 peptide of the influenza A virus showed narrowing of the repertoire with age, possibly impacting the ability to recognize antigenically related viruses”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Gil et al., 2015
Detailed analyses of human TCR repertoires of influenza A virus-specific CD8+ T cells revealed a direct correlation between increasing age and narrowing of the TCR repertoire.
“Detailed analyses of the human TCR repertoires of influenza A virus-specific CD8+ T cells, for instance, revealed a direct correlation between increasing age and narrowing of the TCR repertoire [88].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [88]
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- Authors
- Gil, A., Yassai, M. B., Naumov, Y. N., & Selin, L. K.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Versiti Blood Center of Wisconsin (US)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2015-04-15
- Volume
- 89
- Issue
- 8
- Pages
- 4102-4116
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC4442365
- OpenAlex
- W2152775681
- Cited by
- 78
- References
- 59
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 5 · 2021: 5 · 2020: 14 · 2019: 8 · 2018: 4 · 2017: 12 · 2016: 5 · 2015: 3
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01ai50032-8-0-1)
- U.S. Public Health Service (NIAID NO1-AI-50032)
- National Institute of Allergy and Infectious Diseases (N01 AI050032, U19AI109858, U19AI062627, P01 AI49320, P01AI046629, P01AI049320)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- influenza A virus, T cell receptor repertoire, memory CD8+ T cells, aging, HLA-A2, oligoclonal expansion, CDR3, cross-reactivity, vaccine response prediction, older adults
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Base Sequence, Cloning, Molecular, Humans, Influenza, Human, Middle Aged, Molecular Sequence Data, Influenza A virus, HLA-A2 Antigen, Receptors, Antigen, T-Cell, alpha-beta, Sequence Analysis, DNA, CD8-Positive T-Lymphocytes, Statistics, Nonparametric
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