title: Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade.
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 alphaPD-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.
authors.affiliation: Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Blackburn
authors.forename: Haina
authors.initials: H
authors.lastname: Shin
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001117:Arenaviridae Infections / Q000276:immunology*; D018122:B7-1 Antigen / Q000502:physiology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002908:Chronic Disease; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D010455:Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides