Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection
Abstract Background Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Immunity & Ageing |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12979-023-00365-5 |
| _version_ | 1797752636221423616 |
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| author | Olivia B. Parks Taylor Eddens Jorna Sojati Jie Lan Yu Zhang Tim D. Oury Manda Ramsey John J. Erickson Craig A. Byersdorfer John V. Williams |
| author_facet | Olivia B. Parks Taylor Eddens Jorna Sojati Jie Lan Yu Zhang Tim D. Oury Manda Ramsey John J. Erickson Craig A. Byersdorfer John V. Williams |
| author_sort | Olivia B. Parks |
| collection | DOAJ |
| description | Abstract Background Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses. Results Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1 −/− recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7− TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection. Conclusions This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly. |
| first_indexed | 2024-03-12T17:06:18Z |
| format | Article |
| id | doaj.art-a81277b15295469988f48d8691c5247f |
| institution | Directory Open Access Journal |
| issn | 1742-4933 |
| language | English |
| last_indexed | 2024-03-12T17:06:18Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Immunity & Ageing |
| spelling | doaj.art-a81277b15295469988f48d8691c5247f2023-08-06T11:24:47ZengBMCImmunity & Ageing1742-49332023-08-0120111610.1186/s12979-023-00365-5Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infectionOlivia B. Parks0Taylor Eddens1Jorna Sojati2Jie Lan3Yu Zhang4Tim D. Oury5Manda Ramsey6John J. Erickson7Craig A. Byersdorfer8John V. Williams9Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Allergy/Immunology, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of MedicineDepartment of Pathology, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Neonatology and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of MedicineDepartment of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of MedicineDepartment of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of MedicineAbstract Background Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses. Results Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1 −/− recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7− TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection. Conclusions This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.https://doi.org/10.1186/s12979-023-00365-5Respiratory viral infectionAged immune responseViral immunology |
| spellingShingle | Olivia B. Parks Taylor Eddens Jorna Sojati Jie Lan Yu Zhang Tim D. Oury Manda Ramsey John J. Erickson Craig A. Byersdorfer John V. Williams Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection Immunity & Ageing Respiratory viral infection Aged immune response Viral immunology |
| title | Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection |
| title_full | Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection |
| title_fullStr | Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection |
| title_full_unstemmed | Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection |
| title_short | Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection |
| title_sort | terminally exhausted cd8 t cells contribute to age dependent severity of respiratory virus infection |
| topic | Respiratory viral infection Aged immune response Viral immunology |
| url | https://doi.org/10.1186/s12979-023-00365-5 |
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