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

Department of Immunology and Microbiology

39 Citations (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

Original language	English
Journal	Journal of Immunology
Volume	186
Issue number	2
Pages (from-to)	1068-80
Number of pages	13
ISSN	1550-6606
DOIs	https://doi.org/10.4049/jimmunol.1002212
Publication status	Published - 15 Jan 2011

Keywords

Adult
Aged
Antigens, Bacterial
CD8-Positive T-Lymphocytes
Computational Biology
Epitopes, T-Lymphocyte
Female
Genome, Bacterial
Genome, Human
Humans
Intracellular Fluid
Lymphocyte Activation
Male
Middle Aged
Mycobacterium tuberculosis
Predictive Value of Tests
Tuberculosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, vol. 186, no. 2, pp. 1068-80. https://doi.org/10.4049/jimmunol.1002212

@article{9815d5e0f9a342e2bb322207c975d6ab,

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",

language = "English",

volume = "186",

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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

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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

U2 - 10.4049/jimmunol.1002212

DO - 10.4049/jimmunol.1002212

M3 - Journal article

C2 - 21169544

SN - 1550-6606

VL - 186

SP - 1068

EP - 1080

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

Abstract

Keywords

UN SDGs

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