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

Benjamin H. Gern, Kristin N. Adams, Courtney R. Plumlee, Caleb R. Stoltzfus, Laila Shehata, Albanus O. Moguche, Kathleen Busman-Sahay, Scott G. Hansen, Michael Axthelm, Louis J. Picker, Jacob D. Estes, Kevin B. Urdahl, Michael Y. Gerner

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)594-606.e6
JournalCell Host and Microbe
Volume29
Issue number4
DOIs
StatePublished - Apr 14 2021

Keywords

  • adaptive immunity
  • granuloma
  • IFNɣ
  • immune cell trafficking
  • immune suppression
  • lung inflammation
  • Mycobacterium tuberculosis
  • quantitative imaging
  • T cell function
  • TGFβ

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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