Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis

Cell Host Microbe. 2017 Jun 14;21(6):695-706.e5. doi: 10.1016/j.chom.2017.05.012.


CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection.

Keywords: Ag85B; CD4 T cell; ESAT-6; Mycobacterium tuberculosis; T cell differentiation; antigens; effector T cell; memory T cell; vaccines.

Publication types

  • Clinical Trial

MeSH terms

  • Acyltransferases / immunology
  • Adolescent
  • Animals
  • Antigens, Bacterial / immunology
  • Antigens, Differentiation, T-Lymphocyte / physiology*
  • Bacterial Proteins / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cytokines / blood
  • Female
  • Humans
  • Interferon-gamma / immunology
  • Lung / microbiology
  • Lung / pathology
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / pathogenicity
  • RNA, Messenger / biosynthesis
  • South Africa
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology
  • Tuberculosis / prevention & control
  • Tuberculosis Vaccines / immunology
  • Tuberculosis Vaccines / pharmacology
  • Vaccination


  • Antigens, Bacterial
  • Antigens, Differentiation, T-Lymphocyte
  • Bacterial Proteins
  • Cytokines
  • ESAT-6 protein, Mycobacterium tuberculosis
  • IFNG protein, mouse
  • RNA, Messenger
  • Tuberculosis Vaccines
  • Interferon-gamma
  • Acyltransferases
  • antigen 85B, Mycobacterium tuberculosis