Article ; Online: PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.
ImmunoHorizons
2023 Volume 7, Issue 11, Page(s) 771–787
Abstract: ... yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human ... that improved granzyme B production in aged Pdcd1-/- CD8+ T cells was primarily cell intrinsic because aged wild ... type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD ...
| Abstract | CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells. We sought to elucidate the role of PD-1 signaling on aged CD8+ T cell function and accumulation of CD8+ TRM cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8+ T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1-/- CD8+ T cells was primarily cell intrinsic because aged wild-type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8+ TRM cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8+ TRM cells. These findings suggest that PD-1 signaling impaired CD8+ T cell granzyme B production and contributed to CD8+ TRM cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections. |
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| MeSH term(s) | Animals ; Humans ; Mice ; CD8-Positive T-Lymphocytes ; Granzymes ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; Respiratory Tract Infections ; Virus Diseases |
| Chemical Substances | Granzymes (EC 3.4.21.-) ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor |
| Language | English |
| Publishing date | 2023-11-28 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2573-7732 |
| ISSN (online) | 2573-7732 |
| DOI | 10.4049/immunohorizons.2300094 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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