Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity

Jacob A. Turner, Emmanuel Stephen-Victor, Sen Wang, Magali Noval Rivas, Azza Abdel-Gadir, Hani Harb, Ye Cui, Manoussa Fanny, Louis Marie Charbonnier, Jason Jun Hung Fong, Mehdi Benamar, Leighanne Wang, Oliver T. Burton, Kushagra Bansal, Lynn Bry, Chengsong Zhu, Quan Zhen Li, Rachel L. Clement, Hans C. Oettgen, Elena CrestaniRima Rachid, Peter T. Sage, Talal A. Chatila

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-β1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-β1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.

Original languageEnglish (US)
Pages (from-to)1202-1214.e6
JournalImmunity
Volume53
Issue number6
DOIs
StatePublished - Dec 15 2020

Keywords

  • ROR-γt
  • T follicular helper cells
  • TGF-β
  • allergy
  • autoimmunity
  • checkpoint
  • food allergy
  • mast cells
  • microbiota
  • regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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