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 language | English (US) |
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Pages (from-to) | 1202-1214.e6 |
Journal | Immunity |
Volume | 53 |
Issue number | 6 |
DOIs | |
State | Published - 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