title: Immunodominant West Nile Virus T Cell Epitopes Are Fewer in Number and Fashionably Late.
abstract: Class I HLA molecules mark infected cells for immune targeting by presenting pathogen-encoded peptides on the cell surface. Characterization of viral peptides unique to infected cells is important for understanding CD8(+) T cell responses and for the development of T cell-based immunotherapies. Having previously reported a series of West Nile virus (WNV) epitopes that are naturally presented by HLA-A*02:01, in this study we generated TCR mimic (TCRm) mAbs to three of these peptide/HLA complexes-the immunodominant SVG9 (E protein), the subdominant SLF9 (NS4B protein), and the immunorecessive YTM9 (NS3 protein)-and used these TCRm mAbs to stain WNV-infected cell lines and primary APCs. TCRm staining of WNV-infected cells demonstrated that the immunorecessive YTM9 appeared several hours earlier and at 5- to 10-fold greater density than the more immunogenic SLF9 and SVG9 ligands, respectively. Moreover, staining following inhibition of the TAP demonstrated that all three viral ligands were presented in a TAP-dependent manner despite originating from different cellular compartments. To our knowledge, this study represents the first use of TCRm mAbs to define the kinetics and magnitude of HLA presentation for a series of epitopes encoded by one virus, and the results depict a pattern whereby individual epitopes differ considerably in abundance and availability. The observations that immunodominant ligands can be found at lower levels and at later time points after infection suggest that a reevaluation of the factors that combine to shape T cell reactivity may be warranted.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Saghar
authors.initials: S
authors.lastname: Kaabinejadian
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Curtis P
authors.initials: CP
authors.lastname: McMurtrey
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110;
authors.forename: Sojung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Immunotherapeutic Research, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, TX 79601; Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, TX 79601; Receptor Logic, Inc., Abilene, TX 79601;
authors.forename: Rinki
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Wilfried
authors.initials: W
authors.lastname: Bardet
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Fredda B
authors.initials: FB
authors.lastname: Schafer
authors.affiliation: SensiQ Technologies, Inc., Oklahoma City, OK 73104;
authors.forename: Jason L
authors.initials: JL
authors.lastname: Davenport
authors.affiliation: SensiQ Technologies, Inc., Oklahoma City, OK 73104;
authors.forename: Aaron D
authors.identifier: 0000-0001-6213-7430
authors.initials: AD
authors.lastname: Martin
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110; Department of Medicine, Washington University School of Medicine, St Louis, MO 63110; and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: Center for Immunotherapeutic Research, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, TX 79601; Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, TX 79601; Receptor Logic, Inc., Abilene, TX 79601;
authors.forename: Jon A
authors.initials: JA
authors.lastname: Weidanz
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110;
authors.forename: Ted H
authors.initials: TH
authors.lastname: Hansen
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; William-Hildebrand@ouhsc.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014902:West Nile virus / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell