Abstract
Programmed Death 1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1(high) virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1(high) phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIV-specific CD8 T cell pool. Mathematical modeling of 5-bromo-2' deoxyuridine (BrdU) labeling dynamics demonstrated a significantly increased generation rate of PD-1(high) compared to PD-1(low) CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile whereby only a small fraction of PD-1(high) cells, but virtually all PD-1(low) cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1(high) SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled with a high disappearance rate.
Original language | English (US) |
---|---|
Pages (from-to) | 9836-44 |
Number of pages | 9 |
Journal | Journal of virology |
Volume | 87 |
Issue number | 17 |
DOIs | |
State | Published - Sep 2013 |
Keywords
- Acute Disease
- Animals
- CD8-Positive T-Lymphocytes/immunology
- Cell Proliferation
- Chronic Disease
- Cytokines/biosynthesis
- Immunologic Memory
- Lymphocyte Activation
- Macaca mulatta
- Programmed Cell Death 1 Receptor/metabolism
- Resting Phase, Cell Cycle
- Simian Acquired Immunodeficiency Syndrome/immunology
- Simian Immunodeficiency Virus/immunology
- T-Lymphocyte Subsets/immunology
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't