Regulatory T Cell-Derived TGF-β1 Controls Multiple 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) 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.
Competing Interests: Declaration of Interests L.B., T.C., A.A.-G., and R.R. are inventors on published US patent no. US10391131B2, submitted by The Brigham and Women’s Hospital, Inc. and Children’s Medical Center Corporation, which covers methods and compositions for prevention and treatment of food allergy using microbial treatments. T.C, E.S.-V., A.A.-G. and R.R. have pending patent applications related to the use of probiotics in enforcing oral tolerance in food allergy (no. 62/798,224). L.B., T.C., and R.R. are co-founders of and/or have equity in Paretobio.
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