Abstract
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.
Original language | English (US) |
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Pages (from-to) | 594-606.e6 |
Journal | Cell Host and Microbe |
Volume | 29 |
Issue number | 4 |
DOIs | |
State | Published - Apr 14 2021 |
Keywords
- IFNɣ
- Mycobacterium tuberculosis
- T cell function
- TGFβ
- adaptive immunity
- granuloma
- immune cell trafficking
- immune suppression
- lung inflammation
- quantitative imaging
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology