title: Double- and monofunctional CD4⁺ and CD8⁺ T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals.
abstract: More than 2 billion individuals are latently infected with Mycobacterium tuberculosis (Mtb). Knowledge of the key Mtb antigens and responding T-cell subsets mediating protection against Mtb is critical for developing improved tuberculosis (TB) vaccines. We previously reported that Mtb DosR-regulon-encoded antigens are recognized well by human T cells in association with control of Mtb infection. The characteristics of the responding T-cell subsets, however, remained unidentified. We have therefore studied the cytokine production and memory phenotypes of Mtb DosR-regulon-encoded antigen-specific T cells from individuals who had been infected with Mtb decades ago, yet never developed TB (long-term latent Mtb-infected individuals). Using multi-parameter flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α and IL-2, we found double and single cytokine-producing CD4(+)  as well as CD8(+)  T cells to be the most prominent subsets, particularly IFN-γ(+)  TNF-α(+)  CD8(+)  T cells. The majority of these T cells comprised effector memory and effector T cells. Furthermore, CFSE labeling revealed strong CD4(+)  and CD8(+)  T-cell proliferative responses induced by several "immunodominant" Mtb DosR antigens and their specific peptide epitopes. These findings demonstrate the prominent presence of double- and monofunctional CD4(+)  and CD8(+)  T-cell responses in naturally protected individuals and support the possibility of designing Mtb DosR antigen-based TB vaccines.
authors: Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Susanna
authors: S
authors: Commandeur
authors: May Y
authors: MY
authors: Lin
authors: Krista E
authors: KE
authors: van Meijgaarden
authors: Annemieke H
authors: AH
authors: Friggen
authors: Kees L M C
authors: KL
authors: Franken
authors: Jan W
authors: JW
authors: Drijfhout
authors: Gro E
authors: GE
authors: Korsvold
authors: Fredrik
authors: F
authors: Oftung
authors: Annemieke
authors: A
authors: Geluk
authors: Tom H M
authors: TH
authors: Ottenhoff
mesh_terms: D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D055985:Latent Tuberculosis / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C542863:DosR protein, Mycobacterium tuberculosis; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C072681:Mycobacterium tuberculosis antigens; D007371:Interferon-gamma; D011494:Protein Kinases