Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells
Abstract Memory T cells are a highly heterogeneous collection of antigen-experienced cells that undergo dynamic adaptations upon antigen re-encounter and environmental signals. This heterogeneity hinders studies on memory T cell durability and age-related dysfunction. Using chronic Epstein-Barr viru...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61627-y |
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| author | Ines Sturmlechner Abhinav Jain Bin Hu Rohit R. Jadhav Wenqiang Cao Hirohisa Okuyama Lu Tian Cornelia M. Weyand Jörg J. Goronzy |
| author_facet | Ines Sturmlechner Abhinav Jain Bin Hu Rohit R. Jadhav Wenqiang Cao Hirohisa Okuyama Lu Tian Cornelia M. Weyand Jörg J. Goronzy |
| author_sort | Ines Sturmlechner |
| collection | DOAJ |
| description | Abstract Memory T cells are a highly heterogeneous collection of antigen-experienced cells that undergo dynamic adaptations upon antigen re-encounter and environmental signals. This heterogeneity hinders studies on memory T cell durability and age-related dysfunction. Using chronic Epstein-Barr virus (EBV) infection and barcode-enabled antigen tracing, we assess the influence of age on memory states at the level of single antigen-specific CD8+ T cells. In young adults (<40 years), EBV-specific CD8+ T cells recognizing different antigenic peptides assume divergent preferred differentiation phenotypes. In older adults (>65-years), antigen-specific cells show largely distinct phenotypic and transcriptomic aging trajectories. Common to many albeit not all antigen-specific populations are maintained TCR diversity, gained natural killer cell-like, innate signatures and lost stem-like features while no evidence is seen for cellular senescence or exhaustion. TCR avidity contributes to these phenotypic differences and aging-related changes. Collectively, our data uncover divergent antigen-guided aging shifts in memory T cell phenotypes, which are informative for antigen selection in optimizing vaccine design and adoptive T cell therapy. |
| format | Article |
| id | doaj-art-c9b9a1fa9a764020bfb13f059fa63dd1 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c9b9a1fa9a764020bfb13f059fa63dd12025-08-20T03:05:14ZengNature PortfolioNature Communications2041-17232025-07-0116112110.1038/s41467-025-61627-yAntigen specificity shapes distinct aging trajectories of memory CD8⁺ T cellsInes Sturmlechner0Abhinav Jain1Bin Hu2Rohit R. Jadhav3Wenqiang Cao4Hirohisa Okuyama5Lu Tian6Cornelia M. Weyand7Jörg J. Goronzy8Department of Immunology, Mayo ClinicDepartment of Immunology, Mayo ClinicDepartment of Medicine, Division of Immunology and Rheumatology, Stanford UniversityDepartment of Immunology, Mayo ClinicDepartment of Immunology, Mayo ClinicDepartment of Immunology, Mayo ClinicDepartment of Biomedical Data Science, Stanford UniversityDepartment of Immunology, Mayo ClinicDepartment of Immunology, Mayo ClinicAbstract Memory T cells are a highly heterogeneous collection of antigen-experienced cells that undergo dynamic adaptations upon antigen re-encounter and environmental signals. This heterogeneity hinders studies on memory T cell durability and age-related dysfunction. Using chronic Epstein-Barr virus (EBV) infection and barcode-enabled antigen tracing, we assess the influence of age on memory states at the level of single antigen-specific CD8+ T cells. In young adults (<40 years), EBV-specific CD8+ T cells recognizing different antigenic peptides assume divergent preferred differentiation phenotypes. In older adults (>65-years), antigen-specific cells show largely distinct phenotypic and transcriptomic aging trajectories. Common to many albeit not all antigen-specific populations are maintained TCR diversity, gained natural killer cell-like, innate signatures and lost stem-like features while no evidence is seen for cellular senescence or exhaustion. TCR avidity contributes to these phenotypic differences and aging-related changes. Collectively, our data uncover divergent antigen-guided aging shifts in memory T cell phenotypes, which are informative for antigen selection in optimizing vaccine design and adoptive T cell therapy.https://doi.org/10.1038/s41467-025-61627-y |
| spellingShingle | Ines Sturmlechner Abhinav Jain Bin Hu Rohit R. Jadhav Wenqiang Cao Hirohisa Okuyama Lu Tian Cornelia M. Weyand Jörg J. Goronzy Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells Nature Communications |
| title | Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells |
| title_full | Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells |
| title_fullStr | Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells |
| title_full_unstemmed | Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells |
| title_short | Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells |
| title_sort | antigen specificity shapes distinct aging trajectories of memory cd8⁺ t cells |
| url | https://doi.org/10.1038/s41467-025-61627-y |
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