@article{5586f14c383d4289b3e9a27290c8aeaf,
title = "Regulatory T Cell-Derived TGF-β1 Controls Multiple 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) 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.",
keywords = "ROR-γt, T follicular helper cells, TGF-β, allergy, autoimmunity, checkpoint, food allergy, mast cells, microbiota, regulatory T cells",
author = "Turner, {Jacob A.} and Emmanuel Stephen-Victor and Sen Wang and Rivas, {Magali Noval} and Azza Abdel-Gadir and Hani Harb and Ye Cui and Manoussa Fanny and Charbonnier, {Louis Marie} and Fong, {Jason Jun Hung} and Mehdi Benamar and Leighanne Wang and Burton, {Oliver T.} and Kushagra Bansal and Lynn Bry and Chengsong Zhu and Li, {Quan Zhen} and Clement, {Rachel L.} and Oettgen, {Hans C.} and Elena Crestani and Rima Rachid and Sage, {Peter T.} and Chatila, {Talal A.}",
note = "Funding Information: This work was supported by NIH NIAID grants 5R01AI1269151 and 5R01AI085090 (to T.A.C.) and 5R01AI119918 (to H.C.O), NIDDK grants P30DK056338 (to L.B.) and T32 AI007512 (O.T.B.), the Rao Chakravorti Family Fund (to H.C.O.), the Bunning Foundation (to H.C.O. and T.C.), and DBT/Wellcome Trust India Alliance Intermediate Fellowship IA/I/19/1/504276 (to K.B.). J.A.T. E.S.-V. M.N.R. S.W. and T.C. designed experiments. J.A.T. M.N.R. S.W. J.J.H.F. M.B. A.A.-G. H.H. Y.C. O.T.B. L.-M.C. M.F. and R.L.C. performed experiments and developed experimental models. K.B. analyzed the ATAC-seq data, and C.Z. and Q.-Z.L. analyzed the autoantibody arrays. L.B. provided the Clostridiales consortium. H.C.O. and P.T.S. provided scientific input regarding mast cell and Tfh experiments, respectively. E.C. and R.R. recruited food-allergic and control subjects and provided patient histories and blood samples. E.S.-V. J.A.T. and T.C. wrote the manuscript. 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. Funding Information: This work was supported by NIH NIAID grants 5R01AI1269151 and 5R01AI085090 (to T.A.C.) and 5R01AI119918 (to H.C.O), NIDDK grants P30DK056338 (to L.B.) and T32 AI007512 (O.T.B.), the Rao Chakravorti Family Fund (to H.C.O.), the Bunning Foundation (to H.C.O. and T.C.), and DBT/Wellcome Trust India Alliance Intermediate Fellowship IA/I/19/1/504276 (to K.B.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = dec,
day = "15",
doi = "10.1016/j.immuni.2020.10.002",
language = "English (US)",
volume = "53",
pages = "1202--1214.e6",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}