Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis

Sheila T Tang; Krista E van Meijgaarden; Nadia Caccamo; Giuliana Guggino; Michèl R Klein; Pascale van Weeren; Fatima Kazi; Anette Stryhn Buus; Alexander Zaigler; Ugur Sahin; Søren Buus; Francesco Dieli; Ole Lund; Tom H M Ottenhoff

doi:10.4049/jimmunol.1002212

Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis

Sheila T Tang, Krista E van Meijgaarden, Nadia Caccamo, Giuliana Guggino, Michèl R Klein, Pascale van Weeren, Fatima Kazi, Anette Stryhn Buus, Alexander Zaigler, Ugur Sahin, Søren Buus, Francesco Dieli, Ole Lund, Tom H M Ottenhoff

LUKKET: Institut for Immunologi og Mikrobiologi

39 Citationer (Scopus)

Abstract

Although CD8⁺ T cells help control Mycobacterium tuberculosis infection, their M. tuberculosis Ag repertoire, in vivo frequency, and functionality in human tuberculosis (TB) remains largely undefined.We have performed genome-based bioinformatics searches to identify new M. tuberculosis epitopes presented by major HLA class I supertypes A2, A3, and B7 (covering 80% of the human population). A total of 432 M. tuberculosis peptides predicted to bind to HLA-A*0201, HLA-A*0301, and HLA-B*0702 (representing the above supertypes) were synthesized and HLA-binding affinities determined. Peptide-specific CD8⁺ T cell proliferation assays (CFSE dilution) in 41 M. tuberculosis-responsive donors identified 70 new M. tuberculosis epitopes. Using HLA/peptide tetramers for the 18 most prominently recognized HLA-A*0201-binding M. tuberculosis peptides, recognition by cured TB patients' CD8⁺ T cells was validated for all 18 epitopes. Intracellular cytokine staining for IFN-γ, IL-2, and TNF-α revealed mono-, dual-, as well as triple-positive CD8⁺ T cells, indicating these M. tuberculosis peptide-specific CD8⁺ T cells were (poly)functional. Moreover, these T cells were primed during natural infection, because they were absent from M. tuberculosis-noninfected individuals. Control CMV peptide/HLA-A*0201 tetramers stained CD8⁺ T cells in M. tuberculosis-infected and noninfected individuals equally, whereas Ebola peptide/HLA-A*0201 tetramers were negative. In conclusion, the M. tuberculosis-epitope/Ag repertoire for human CD8⁺ T cells is much broader than hitherto suspected, and the newly identified M. tuberculosis Ags are recognized by (poly)functional CD8⁺ T cells during control of infection. These results impact on TB-vaccine design and biomarker identification. Copyright

Originalsprog	Engelsk
Tidsskrift	Journal of Immunology
Vol/bind	186
Udgave nummer	2
Sider (fra-til)	1068-80
Antal sider	13
ISSN	1550-6606
DOI	https://doi.org/10.4049/jimmunol.1002212
Status	Udgivet - 15 jan. 2011

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10.4049/jimmunol.1002212

https://www.jimmunol.org/content/jimmunol/186/2/1068.full.pdf

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Tang, S. T., van Meijgaarden, K. E., Caccamo, N., Guggino, G., Klein, M. R., van Weeren, P., Kazi, F., Buus, A. S., Zaigler, A., Sahin, U., Buus, S., Dieli, F., Lund, O., & Ottenhoff, T. H. M. (2011). Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis. Journal of Immunology, 186(2), 1068-80. https://doi.org/10.4049/jimmunol.1002212

Tang, ST, van Meijgaarden, KE, Caccamo, N, Guggino, G, Klein, MR, van Weeren, P, Kazi, F, Buus, AS, Zaigler, A, Sahin, U, Buus, S, Dieli, F, Lund, O & Ottenhoff, THM 2011, 'Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis', Journal of Immunology, bind 186, nr. 2, s. 1068-80. https://doi.org/10.4049/jimmunol.1002212

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title = "Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis",

abstract = "Although CD8+ T cells help control Mycobacterium tuberculosis infection, their M. tuberculosis Ag repertoire, in vivo frequency, and functionality in human tuberculosis (TB) remains largely undefined.We have performed genome-based bioinformatics searches to identify new M. tuberculosis epitopes presented by major HLA class I supertypes A2, A3, and B7 (covering 80% of the human population). A total of 432 M. tuberculosis peptides predicted to bind to HLA-A*0201, HLA-A*0301, and HLA-B*0702 (representing the above supertypes) were synthesized and HLA-binding affinities determined. Peptide-specific CD8+ T cell proliferation assays (CFSE dilution) in 41 M. tuberculosis-responsive donors identified 70 new M. tuberculosis epitopes. Using HLA/peptide tetramers for the 18 most prominently recognized HLA-A*0201-binding M. tuberculosis peptides, recognition by cured TB patients' CD8+ T cells was validated for all 18 epitopes. Intracellular cytokine staining for IFN-γ, IL-2, and TNF-α revealed mono-, dual-, as well as triple-positive CD8+ T cells, indicating these M. tuberculosis peptide-specific CD8+ T cells were (poly)functional. Moreover, these T cells were primed during natural infection, because they were absent from M. tuberculosis-noninfected individuals. Control CMV peptide/HLA-A*0201 tetramers stained CD8+ T cells in M. tuberculosis-infected and noninfected individuals equally, whereas Ebola peptide/HLA-A*0201 tetramers were negative. In conclusion, the M. tuberculosis-epitope/Ag repertoire for human CD8+ T cells is much broader than hitherto suspected, and the newly identified M. tuberculosis Ags are recognized by (poly)functional CD8+ T cells during control of infection. These results impact on TB-vaccine design and biomarker identification. Copyright",

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author = "Tang, {Sheila T} and {van Meijgaarden}, {Krista E} and Nadia Caccamo and Giuliana Guggino and Klein, {Mich{\`e}l R} and {van Weeren}, Pascale and Fatima Kazi and Buus, {Anette Stryhn} and Alexander Zaigler and Ugur Sahin and S{\o}ren Buus and Francesco Dieli and Ole Lund and Ottenhoff, {Tom H M}",

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doi = "10.4049/jimmunol.1002212",

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AU - Tang, Sheila T

AU - van Meijgaarden, Krista E

AU - Caccamo, Nadia

AU - Guggino, Giuliana

AU - Klein, Michèl R

AU - van Weeren, Pascale

AU - Kazi, Fatima

AU - Buus, Anette Stryhn

AU - Zaigler, Alexander

AU - Sahin, Ugur

AU - Buus, Søren

AU - Dieli, Francesco

AU - Lund, Ole

AU - Ottenhoff, Tom H M

PY - 2011/1/15

Y1 - 2011/1/15

N2 - Although CD8+ T cells help control Mycobacterium tuberculosis infection, their M. tuberculosis Ag repertoire, in vivo frequency, and functionality in human tuberculosis (TB) remains largely undefined.We have performed genome-based bioinformatics searches to identify new M. tuberculosis epitopes presented by major HLA class I supertypes A2, A3, and B7 (covering 80% of the human population). A total of 432 M. tuberculosis peptides predicted to bind to HLA-A*0201, HLA-A*0301, and HLA-B*0702 (representing the above supertypes) were synthesized and HLA-binding affinities determined. Peptide-specific CD8+ T cell proliferation assays (CFSE dilution) in 41 M. tuberculosis-responsive donors identified 70 new M. tuberculosis epitopes. Using HLA/peptide tetramers for the 18 most prominently recognized HLA-A*0201-binding M. tuberculosis peptides, recognition by cured TB patients' CD8+ T cells was validated for all 18 epitopes. Intracellular cytokine staining for IFN-γ, IL-2, and TNF-α revealed mono-, dual-, as well as triple-positive CD8+ T cells, indicating these M. tuberculosis peptide-specific CD8+ T cells were (poly)functional. Moreover, these T cells were primed during natural infection, because they were absent from M. tuberculosis-noninfected individuals. Control CMV peptide/HLA-A*0201 tetramers stained CD8+ T cells in M. tuberculosis-infected and noninfected individuals equally, whereas Ebola peptide/HLA-A*0201 tetramers were negative. In conclusion, the M. tuberculosis-epitope/Ag repertoire for human CD8+ T cells is much broader than hitherto suspected, and the newly identified M. tuberculosis Ags are recognized by (poly)functional CD8+ T cells during control of infection. These results impact on TB-vaccine design and biomarker identification. Copyright

AB - Although CD8+ T cells help control Mycobacterium tuberculosis infection, their M. tuberculosis Ag repertoire, in vivo frequency, and functionality in human tuberculosis (TB) remains largely undefined.We have performed genome-based bioinformatics searches to identify new M. tuberculosis epitopes presented by major HLA class I supertypes A2, A3, and B7 (covering 80% of the human population). A total of 432 M. tuberculosis peptides predicted to bind to HLA-A*0201, HLA-A*0301, and HLA-B*0702 (representing the above supertypes) were synthesized and HLA-binding affinities determined. Peptide-specific CD8+ T cell proliferation assays (CFSE dilution) in 41 M. tuberculosis-responsive donors identified 70 new M. tuberculosis epitopes. Using HLA/peptide tetramers for the 18 most prominently recognized HLA-A*0201-binding M. tuberculosis peptides, recognition by cured TB patients' CD8+ T cells was validated for all 18 epitopes. Intracellular cytokine staining for IFN-γ, IL-2, and TNF-α revealed mono-, dual-, as well as triple-positive CD8+ T cells, indicating these M. tuberculosis peptide-specific CD8+ T cells were (poly)functional. Moreover, these T cells were primed during natural infection, because they were absent from M. tuberculosis-noninfected individuals. Control CMV peptide/HLA-A*0201 tetramers stained CD8+ T cells in M. tuberculosis-infected and noninfected individuals equally, whereas Ebola peptide/HLA-A*0201 tetramers were negative. In conclusion, the M. tuberculosis-epitope/Ag repertoire for human CD8+ T cells is much broader than hitherto suspected, and the newly identified M. tuberculosis Ags are recognized by (poly)functional CD8+ T cells during control of infection. These results impact on TB-vaccine design and biomarker identification. Copyright

KW - Adult

KW - Aged

KW - Antigens, Bacterial

KW - CD8-Positive T-Lymphocytes

KW - Computational Biology

KW - Epitopes, T-Lymphocyte

KW - Female

KW - Genome, Bacterial

KW - Genome, Human

KW - Humans

KW - Intracellular Fluid

KW - Lymphocyte Activation

KW - Male

KW - Middle Aged

KW - Mycobacterium tuberculosis

KW - Predictive Value of Tests

KW - Tuberculosis

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DO - 10.4049/jimmunol.1002212

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JO - Journal of Immunology

JF - Journal of Immunology

IS - 2

ER -

Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis

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