Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade

Shawn D. Blackburn, Haina Shin, Gordon J. Freeman, E. John Wherry

Research output: Contribution to journalArticle

255 Scopus citations

Abstract

Programmed death-1 (PD-1) regulates T cell exhaustion during chronic infections. Blocking the PD-1:PD-ligand (PD-L) pathway reinvigorates exhausted CD8 T cells. Exactly how blocking PD-1:PD-L interactions improves T cell immunity, however, remains unclear. PD-1:PD-L blockade could reprogram all exhausted T cells to become antiviral effectors. Alternatively, this blockade might selectively expand a subset of exhausted T cells. We have identified two subpopulations of exhausted CD8 T cells during chronic viral infection in mice. One subset of exhausted CD8 T cells is rescued by αPD-L1 blockade, whereas the other subset appears more terminally differentiated and responds poorly to PD-1:PD-L blockade. Blocking PD-1:PD-L interactions reduces spontaneous apoptosis and enhances expansion and protective immunity of the rescuable subset, but not the more terminally differentiated subset of exhausted CD8 T cells. These results have implications for predicting clinical responses to PD-1-based therapeutic interventions and for understanding T cell dynamics during persisting infections.

Original languageEnglish
Pages (from-to)15016-15021
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number39
DOIs
StatePublished - Sep 30 2008
Externally publishedYes

Keywords

  • Chronic infection
  • Lymphocytic choriomeningitis virus
  • PD-1
  • T cell exhaustion
  • T cell memory

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