title: Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection.
abstract: During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1(lo) functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V-->A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1(hi) and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Robbert G
authors.initials: RG
authors.lastname: van der Most
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000302:isolation & purification; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017186:Titrimetry; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D053699:Interleukin-7 Receptor alpha Subunit; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus