Discovering naturally processed antigenic determinants that confer protective T cell immunity

Pavlo Gilchuk, Charles T. Spencer, Stephanie B. Conant, Timothy Hill, Jennifer J. Gray, Xinnan Niu, Mu Zheng, John J. Erickson, Kelli L. Boyd, K. Jill McAfee, Carla Oseroff, Sine Reker Hadrup, Jack R. Bennink, William Hildebrand, Kathryn M. Edwards, James E. Crowe, John V. Williams, Søren Buus, Alessandro Sette, Ton N. M. SchumacherAndrew J. Link, Sebastian Joyce

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

CD8(+) T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.
Original languageEnglish
JournalJournal of Clinical Investigation
Volume123
Issue number5
Pages (from-to)1976-1987
Number of pages12
ISSN0021-9738
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • Animals
  • Antigen Presentation
  • Antigens
  • CD8-Positive T-Lymphocytes
  • Epitopes
  • Epitopes, T-Lymphocyte
  • HeLa Cells
  • Histocompatibility Antigens Class I
  • Humans
  • Immunodominant Epitopes
  • Mass Spectrometry
  • Mice
  • Mice, Transgenic
  • Peptides
  • Phenotype
  • T-Lymphocytes
  • Vaccinia virus
  • Medicine (all)
  • epitope
  • HLA antigen class 1
  • proteome
  • animal cell
  • animal model
  • animal tissue
  • antigenicity
  • article
  • blood
  • CD8+ T lymphocyte
  • cellular immunity
  • controlled study
  • enzyme linked immunospot assay
  • lymphocyte homing
  • mass spectrometry
  • mouse
  • nonhuman
  • phenotype
  • priority journal
  • proteomics
  • smallpox
  • MEDICINE,
  • HLA-B-ASTERISK-0702 TRANSGENIC MICE
  • VACCINIA VIRUS
  • MALARIA VACCINE
  • IN-VIVO
  • MEDIATED PROTECTION
  • RESPONSE MAGNITUDE
  • SMALLPOX VACCINES
  • MASS-SPECTROMETRY
  • MEMORY
  • PROTEIN
  • DNA and RNA Reverse Transcribing Viruses Viruses Microorganisms (DNA and RNA Reverse Transcribing Viruses, Microorganisms, Viruses) - Retroviridae [03305] HIV common Human immunodeficiency virus species pathogen
  • dsDNA Viruses Viruses Microorganisms (Double-Stranded DNA Viruses, Microorganisms, Viruses) - Herpesviridae [03115] Cytomegalovirus genus pathogen
  • dsDNA Viruses Viruses Microorganisms (Double-Stranded DNA Viruses, Microorganisms, Viruses) - Poxviridae [03110] Vaccinia virus species
  • Mycobacteria Actinomycetes and Related Organisms Eubacteria Bacteria Microorganisms (Bacteria, Eubacteria, Microorganisms) - Mycobacteriaceae [08881] Mycobacterium tuberculosis species pathogen
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HeLa cell line cell_line human cervix carcinoma cells
  • Protozoa Invertebrata Animalia (Animals, Invertebrates, Microorganisms, Protozoans) - Sporozoa [35400] Plasmodium genus pathogen
  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common host
  • HLA class I
  • smallpox vaccine antiinfective-drug, antiviral-drug vaccine pharmacodynamics, efficacy
  • vaccinia virus antigenic determinant based vaccine antiinfective-drug, antiviral-drug vaccine pharmacodynamics, efficacy
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 12512, Pathology - Therapy
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 31000, Physiology and biochemistry of bacteria
  • 33502, Virology - General and methods
  • 34502, Immunology - General and methods
  • 36006, Medical and clinical microbiology - Virology
  • 38502, Chemotherapy - General, methods and metabolism
  • 38506, Chemotherapy - Antiviral agents
  • 64002, Invertebrata: comparative, experimental morphology, physiology and pathology - Protozoa
  • Immune System
  • Infection
  • Pharmacology
  • vaccinia virus infection Vaccinia (MeSH) viral disease prevention and control
  • immunologic characterization
  • large-scale discovery
  • Chemical Coordination and Homeostasis
  • CD8 positive T cell immune system
  • peripheral blood cell blood and lymphatics
  • T cell immune system, blood and lymphatics
  • proteomic-based approach laboratory techniques, genetic techniques
  • CELLULAR immunity

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