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 R Hadrup; Jack R Bennink; William Hildebrand; Kathryn M Edwards; James E Crowe; John V Williams; Søren Buus; Alessandro Sette; Ton N M Schumacher; Andrew J Link; Sebastian Joyce

doi:10.1172/JCI67388

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 R 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

LUKKET: Institut for Immunologi og Mikrobiologi

43 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of Clinical Investigation
Vol/bind	123
Udgave nummer	5
Sider (fra-til)	1976-87
Antal sider	12
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI67388
Status	Udgivet - 1 maj 2013

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10.1172/JCI67388

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Gilchuk, P., Spencer, C. T., Conant, S. B., Hill, T., Gray, J. J., Niu, X., Zheng, M., Erickson, J. J., Boyd, K. L., McAfee, K. J., Oseroff, C., Hadrup, S. R., Bennink, J. R., Hildebrand, W., Edwards, K. M., Crowe, J. E., Williams, J. V., Buus, S., Sette, A., ... Joyce, S. (2013). Discovering naturally processed antigenic determinants that confer protective T cell immunity. The Journal of Clinical Investigation, 123(5), 1976-87. https://doi.org/10.1172/JCI67388

Gilchuk, P, Spencer, CT, Conant, SB, Hill, T, Gray, JJ, Niu, X, Zheng, M, Erickson, JJ, Boyd, KL, McAfee, KJ, Oseroff, C, Hadrup, SR, Bennink, JR, Hildebrand, W, Edwards, KM, Crowe, JE, Williams, JV, Buus, S, Sette, A, Schumacher, TNM, Link, AJ & Joyce, S 2013, 'Discovering naturally processed antigenic determinants that confer protective T cell immunity', The Journal of Clinical Investigation, bind 123, nr. 5, s. 1976-87. https://doi.org/10.1172/JCI67388

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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.",

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",

author = "Pavlo Gilchuk and Spencer, {Charles T} and Conant, {Stephanie B} and Timothy Hill and Gray, {Jennifer J} and Xinnan Niu and Mu Zheng and Erickson, {John J} and Boyd, {Kelli L} and McAfee, {K Jill} and Carla Oseroff and Hadrup, {Sine R} and Bennink, {Jack R} and William Hildebrand and Edwards, {Kathryn M} and Crowe, {James E} and Williams, {John V} and S{\o}ren Buus and Alessandro Sette and Schumacher, {Ton N M} and Link, {Andrew J} and Sebastian Joyce",

year = "2013",

month = may,

day = "1",

doi = "10.1172/JCI67388",

language = "English",

volume = "123",

pages = "1976--87",

journal = "Journal of Clinical Investigation",

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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

SN - 0021-9738

VL - 123

SP - 1976

EP - 1987

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 5

ER -

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Abstract

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