Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis
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Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis. / Tang, Sheila T; van Meijgaarden, Krista E; Caccamo, Nadia; Guggino, Giuliana; Klein, Michèl R; van Weeren, Pascale; Kazi, Fatima; Buus, Anette Stryhn; Zaigler, Alexander; Sahin, Ugur; Buus, Søren; Dieli, Francesco; Lund, Ole; Ottenhoff, Tom H M.
I: Journal of Immunology, Bind 186, Nr. 2, 2011, s. 1068-80.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genome-based in silico identification of new Mycobacterium tuberculosis antigens activating polyfunctional CD8+ T cells in human tuberculosis
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
Y1 - 2011
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-¿, IL-2, and TNF-a 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.
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-¿, IL-2, and TNF-a 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.
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
VL - 186
SP - 1068
EP - 1080
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -
ID: 40354425