Double- and monofunctional CD4⁺ and CD8⁺ T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals

Eur J Immunol. 2011 Oct;41(10):2925-36. doi: 10.1002/eji.201141602. Epub 2011 Aug 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, Bacterial / immunology
  • Bacterial Proteins / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • DNA-Binding Proteins
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / biosynthesis
  • Latent Tuberculosis / immunology*
  • Latent Tuberculosis / microbiology
  • Lymphocyte Activation / immunology
  • Middle Aged
  • Mycobacterium tuberculosis / immunology*
  • Protein Kinases / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Antigens, Bacterial
  • Bacterial Proteins
  • DNA-Binding Proteins
  • DosR protein, Mycobacterium tuberculosis
  • Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Mycobacterium tuberculosis antigens
  • Interferon-gamma
  • Protein Kinases