Discovering naturally processed antigenic determinants that confer protective T cell immunity
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Discovering naturally processed antigenic determinants that confer protective T cell immunity. / Gilchuk, Pavlo; Spencer, Charles T; Conant, Stephanie B; Hill, Timothy; Gray, Jennifer J; Niu, Xinnan; Zheng, Mu; Erickson, John J; Boyd, Kelli L; McAfee, K Jill; Oseroff, Carla; Hadrup, Sine R; Bennink, Jack R; Hildebrand, William; Edwards, Kathryn M; Crowe, James E; Williams, John V; Buus, Søren; Sette, Alessandro; Schumacher, Ton N M; Link, Andrew J; Joyce, Sebastian.
In: The Journal of Clinical Investigation, Vol. 123, No. 5, 01.05.2013, p. 1976-87.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovering naturally processed antigenic determinants that confer protective T cell immunity
AU - Gilchuk, Pavlo
AU - Spencer, Charles T
AU - Conant, Stephanie B
AU - Hill, Timothy
AU - Gray, Jennifer J
AU - Niu, Xinnan
AU - Zheng, Mu
AU - Erickson, John J
AU - Boyd, Kelli L
AU - McAfee, K Jill
AU - Oseroff, Carla
AU - Hadrup, Sine R
AU - Bennink, Jack R
AU - Hildebrand, William
AU - Edwards, Kathryn M
AU - Crowe, James E
AU - Williams, John V
AU - Buus, Søren
AU - Sette, Alessandro
AU - Schumacher, Ton N M
AU - Link, Andrew J
AU - Joyce, Sebastian
PY - 2013/5/1
Y1 - 2013/5/1
N2 - 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.
AB - 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.
KW - Animals
KW - Antigen Presentation
KW - Antigens
KW - CD8-Positive T-Lymphocytes
KW - Epitopes
KW - Epitopes, T-Lymphocyte
KW - HeLa Cells
KW - Histocompatibility Antigens Class I
KW - Humans
KW - Immunodominant Epitopes
KW - Mass Spectrometry
KW - Mice
KW - Mice, Transgenic
KW - Peptides
KW - Phenotype
KW - T-Lymphocytes
KW - Vaccinia virus
U2 - 10.1172/JCI67388
DO - 10.1172/JCI67388
M3 - Journal article
C2 - 23543059
VL - 123
SP - 1976
EP - 1987
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -
ID: 49595355