Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity

Jacob A. Turner; Emmanuel Stephen-Victor; Sen Wang; Magali Noval Rivas; Azza Abdel-Gadir; Hani Harb; Ye Cui; Manoussa Fanny; Louis Marie Charbonnier; Jason Jun Hung Fong; Mehdi Benamar; Leighanne Wang; Oliver T. Burton; Kushagra Bansal; Lynn Bry; Chengsong Zhu; Quan Zhen Li; Rachel L. Clement; Hans C. Oettgen; Elena Crestani; Rima Rachid; Peter T. Sage; Talal A. Chatila

doi:10.1016/j.immuni.2020.10.002

Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity

Jacob A. Turner, Emmanuel Stephen-Victor, Sen Wang, Magali Noval Rivas, Azza Abdel-Gadir, Hani Harb, Ye Cui, Manoussa Fanny, Louis Marie Charbonnier, Jason Jun Hung Fong, Mehdi Benamar, Leighanne Wang, Oliver T. Burton, Kushagra Bansal, Lynn Bry, Chengsong Zhu, Quan Zhen Li, Rachel L. Clement, Hans C. Oettgen, Elena CrestaniRima Rachid, Peter T. Sage, Talal A. Chatila

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1202-1214.e6
Journal	Immunity
Volume	53
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2020.10.002
State	Published - Dec 15 2020

Keywords

ROR-γt
T follicular helper cells
TGF-β
allergy
autoimmunity
checkpoint
food allergy
mast cells
microbiota
regulatory T cells

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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Turner, J. A., Stephen-Victor, E., Wang, S., Rivas, M. N., Abdel-Gadir, A., Harb, H., Cui, Y., Fanny, M., Charbonnier, L. M., Fong, J. J. H., Benamar, M., Wang, L., Burton, O. T., Bansal, K., Bry, L., Zhu, C., Li, Q. Z., Clement, R. L., Oettgen, H. C., ... Chatila, T. A. (2020). Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. Immunity, 53(6), 1202-1214.e6. https://doi.org/10.1016/j.immuni.2020.10.002

Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. / Turner, Jacob A.; Stephen-Victor, Emmanuel; Wang, Sen; Rivas, Magali Noval; Abdel-Gadir, Azza; Harb, Hani; Cui, Ye; Fanny, Manoussa; Charbonnier, Louis Marie; Fong, Jason Jun Hung; Benamar, Mehdi; Wang, Leighanne; Burton, Oliver T.; Bansal, Kushagra; Bry, Lynn; Zhu, Chengsong; Li, Quan Zhen; Clement, Rachel L.; Oettgen, Hans C.; Crestani, Elena; Rachid, Rima; Sage, Peter T.; Chatila, Talal A.

In: Immunity, Vol. 53, No. 6, 15.12.2020, p. 1202-1214.e6.

Research output: Contribution to journal › Article › peer-review

Turner, JA, Stephen-Victor, E, Wang, S, Rivas, MN, Abdel-Gadir, A, Harb, H, Cui, Y, Fanny, M, Charbonnier, LM, Fong, JJH, Benamar, M, Wang, L, Burton, OT, Bansal, K, Bry, L, Zhu, C, Li, QZ, Clement, RL, Oettgen, HC, Crestani, E, Rachid, R, Sage, PT & Chatila, TA 2020, 'Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity', Immunity, vol. 53, no. 6, pp. 1202-1214.e6. https://doi.org/10.1016/j.immuni.2020.10.002

Turner, Jacob A. ; Stephen-Victor, Emmanuel ; Wang, Sen ; Rivas, Magali Noval ; Abdel-Gadir, Azza ; Harb, Hani ; Cui, Ye ; Fanny, Manoussa ; Charbonnier, Louis Marie ; Fong, Jason Jun Hung ; Benamar, Mehdi ; Wang, Leighanne ; Burton, Oliver T. ; Bansal, Kushagra ; Bry, Lynn ; Zhu, Chengsong ; Li, Quan Zhen ; Clement, Rachel L. ; Oettgen, Hans C. ; Crestani, Elena ; Rachid, Rima ; Sage, Peter T. ; Chatila, Talal A. / Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. In: Immunity. 2020 ; Vol. 53, No. 6. pp. 1202-1214.e6.

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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.). ",

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doi = "10.1016/j.immuni.2020.10.002",

language = "English (US)",

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T1 - Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity

AU - Turner, Jacob A.

AU - Stephen-Victor, Emmanuel

AU - Wang, Sen

AU - Rivas, Magali Noval

AU - Abdel-Gadir, Azza

AU - Harb, Hani

AU - Cui, Ye

AU - Fanny, Manoussa

AU - Charbonnier, Louis Marie

AU - Fong, Jason Jun Hung

AU - Benamar, Mehdi

AU - Wang, Leighanne

AU - Burton, Oliver T.

AU - Bansal, Kushagra

AU - Bry, Lynn

AU - Zhu, Chengsong

AU - Li, Quan Zhen

AU - Clement, Rachel L.

AU - Oettgen, Hans C.

AU - Crestani, Elena

AU - Rachid, Rima

AU - Sage, Peter T.

AU - Chatila, Talal A.

N1 - 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.).

PY - 2020/12/15

Y1 - 2020/12/15

N2 - 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.

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KW - food allergy

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KW - microbiota

KW - regulatory T cells

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