TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma

Cell Host Microbe. 2021 Apr 14;29(4):594-606.e6. doi: 10.1016/j.chom.2021.02.005. Epub 2021 Mar 11.


CD4 T cell effector function is required for optimal containment of Mycobacterium tuberculosis (Mtb) infection. IFNɣ produced by CD4 T cells is a key cytokine that contributes to protection. However, lung-infiltrating CD4 T cells have a limited ability to produce IFNɣ, and IFNɣ plays a lesser protective role within the lung than at sites of Mtb dissemination. In a murine infection model, we observed that IFNɣ production by Mtb-specific CD4 T cells is rapidly extinguished within the granuloma but not within unaffected lung regions, suggesting localized immunosuppression. We identified a signature of TGFβ signaling within granuloma-infiltrating T cells in both mice and rhesus macaques. Selective blockade of TGFβ signaling in T cells resulted in an accumulation of terminally differentiated effector CD4 T cells, improved IFNɣ production within granulomas, and reduced bacterial burdens. These findings uncover a spatially localized immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.

Keywords: IFNɣ; Mycobacterium tuberculosis; T cell function; TGFβ; adaptive immunity; granuloma; immune cell trafficking; immune suppression; lung inflammation; quantitative imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • CD4-Positive T-Lymphocytes
  • Cell Death
  • Cytokines
  • Disease Models, Animal
  • Female
  • Granuloma / immunology*
  • Granuloma / microbiology
  • Inflammation
  • Interferon-gamma
  • Lung / microbiology
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis
  • T-Lymphocytes / immunology*
  • Th1 Cells
  • Transforming Growth Factor beta / metabolism*
  • Tuberculosis / immunology*


  • Cytokines
  • Transforming Growth Factor beta
  • Interferon-gamma