Treg Cell TGF-β1 Regulates Distinct Checkpoints Governing Allergy and Autoimmunity

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. We employed FA-prone mice that carry a gain of function mutation in the IL-4Ra chain gene (Il4raF709) to investigate the mechanisms by which FA develops in these mice. Epigenetic analysis of mesenteric lymph node Treg cells isolated from Il4raF709 mice using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed decreased access at the Tgfb1 locus, which was reversed by deletion of Stat6.