Regulatory T Cell TGF-B1 Regulates Distinct Checkpoints Governing Allergy and Autoimmunity

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) have decreased expression of transforming growth factor beta 1 (TGF- b1) due to IL-4 and STAT6-dependent inhibition of Tgfb1 transcription. These changes were modelled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota dependent ROR-gt+ 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 for Treg cell-derived TGF- b1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose and microbiota-dependent manner.