Gilchuk, Pavlo3; Spencer, Charles T3; Conant, Stephanie B3; Hill, Timothy3; Gray, Jennifer J3; Niu, Xinnan3; Zheng, Mu3; Erickson, John J3; Boyd, Kelli L3; McAfee, K Jill3; Oseroff, Carla3; Hadrup, Sine R5; Bennink, Jack R3; Hildebrand, William3; Edwards, Kathryn M3; Crowe, James E3; Williams, John V3; Buus, Søren6; Sette, Alessandro3; Schumacher, Ton N M3; Link, Andrew J3; Joyce, Sebastian3
1 Graduate School of Health and Medical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet5 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Journal of Clinical Investigation, 2013, Vol 123, Issue 5, p. 1976-87
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; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural