title: Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans.
abstract: Rhinovirus (RV) is a major cause of common cold and an important trigger of acute episodes of chronic lung diseases. Antigenic variation across the numerous RV strains results in frequent infections and a lack of durable cross-protection. Because the nature of human CD4+T cells that target RV is largely unknown, T cell epitopes of RV capsid proteins were analyzed, and cognate T cells were characterized in healthy subjects and those infected by intranasal challenge. Peptide epitopes of the RV-A16 capsid proteins VP1 and VP2 were identified by peptide/MHC class II tetramer-guided epitope mapping, validated by direct ex vivo enumeration, and interrogated using a variety of in silico methods. Among noninfected subjects, those circulating RV-A16-specific CD4+T cells detected at the highest frequencies targeted 10 unique epitopes that bound to diverse HLA-DR molecules. T cell epitopes localized to conserved molecular regions of biological significance to the virus were enriched for HLA class I and II binding motifs, and constituted both species-specific (RV-A) and pan-species (RV-A, -B, and -C) varieties. Circulating epitope-specific T cells comprised both memory Th1 and T follicular helper cells, and were rapidly expanded and activated after intranasal challenge with RV-A16. Cross-reactivity was evidenced by identification of a common *0401-restricted epitope for RV-A16 and RV-A39 by tetramer-guided epitope mapping and the ability for RV-A16-specific Th1 cells to proliferate in response to their RV-A39 peptide counterpart. The preferential persistence of high-frequency RV-specific memory Th1 cells that recognize a limited set of conserved epitopes likely arises from iterative priming by previous exposures to different RV strains.
authors: Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors: Lyndsey M
authors: 0000-0003-3203-3264
authors: LM
authors: Muehling
authors: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.
authors: Duy T
authors: DT
authors: Mai
authors: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.
authors: William W
authors: WW
authors: Kwok
authors: Department of Pediatrics, University of Virginia Health System, Charlottesville, VA 22908; and.
authors: Peter W
authors: PW
authors: Heymann
authors: Indoor Biotechnologies Inc., Charlottesville, VA 22903.
authors: Anna
authors: 0000-0002-8729-1829
authors: A
authors: Pomés
authors: Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908; jaw4m@virginia.edu.
authors: Judith A
authors: JA
authors: Woodfolk
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008875:Middle Aged; D010850:Picornaviridae Infections / Q000276:immunology*; D012229:Rhinovirus / Q000276:immunology*; D055815:Young Adult
chemical_list: D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte