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RESEARCH PRODUCT

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

Sheila Tuyet TangNadia CaccamoFatima KaziUgur SahinFrancesco DieliOle LundMichèl R. KleinAlexander Dr. ZaiglerSøren BuusPascale Van WeerenTom H. M. OttenhoffGiuliana GugginoKrista E. Van MeijgaardenAnette Stryhn

subject

AdultIntracellular FluidMaleTuberculosisT cellImmunologyEpitopes T-LymphocyteHuman leukocyte antigenCD8-Positive T-LymphocytesLymphocyte ActivationEpitopeTuberculosis CD8 T cells cytokinesMycobacterium tuberculosis03 medical and health sciencesAntigenifn-gamma protective efficacy binding-affinity dormancy regulon subunit vaccine transgenic mice hla-b epitopes infection responsesPredictive Value of TestsmedicineImmunology and AllergyCytotoxic T cellHumansTuberculosis030304 developmental biologyAged0303 health sciencesAntigens Bacterialbiology030306 microbiologyGenome HumanComputational BiologyMycobacterium tuberculosisMiddle Agedbiology.organism_classificationmedicine.diseaseVirology3. Good healthmedicine.anatomical_structureFemaleCD8Genome Bacterial

description

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-gamma, IL-2, and TNF-alpha 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. The Journal of Immunology, 2011, 186: 1068-1080.

yearjournalcountryeditionlanguage
2011-01-15Journal of immunology (Baltimore, Md. : 1950)
10.4049/jimmunol.1002212https://pubmed.ncbi.nlm.nih.gov/21169544