GSE158804
Treg Cell TGF-ß1 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. Overall design: 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.