High production rates sustain in vivo levels of PD-1high simian immunodeficiency virus-specific CD8 T cells in the face of rapid clearance

Constantinos Petrovas, Takuya Yamamoto, David A Price, Srinivas S Rao, Nichole R Klatt, Jason M Brenchley, Daniel C Douek, Emma Gostick, Bastian R Angermann, Zvi Grossman, Derek C Macallan, Martin Meier-Schellersheim, Richard A Koup

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)9836-44
Number of pages9
JournalJournal of virology
Volume87
Issue number17
DOIs
StatePublished - 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

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