title: Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load.
abstract: OBJECTIVE
  Although CD8+ T cells play a critical role in the control of HIV-1 infection,their antiviral efficacy can be limited by antigenic variation and immune exhaustion.The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells.
  
  
  METHODS
  Here, we used an array of different human leukocyte antigen(HLA)-B*15:03 and HLA-B*42:01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8+ T-cell populations(n = 128) spanning 11 different epitope targets.
  
  
  RESULTS
  Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8+ T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8+ T cells.
  
  
  CONCLUSIONS
  Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure.
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.forename: Reuben
authors.initials: R
authors.lastname: McGregor
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Catherine
authors.initials: C
authors.lastname: Koofhethile
authors.forename: Jacqui
authors.initials: J
authors.lastname: Brener
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.forename: Luzzi
authors.initials: L
authors.lastname: Graziano
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell