Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity

Mattias Nd Svensson, Karen M. Doody, Benjamin J. Schmiedel, Sourya Bhattacharyya, Bharat Panwar, Florian Wiede, Shen Yang, Eugenio Santelli, Dennis J. Wu, Cristiano Sacchetti, Ravindra Gujar, Gregory Seumois, William B. Kiosses, Isabelle Aubry, Gisen Kim, Piotr Mydel, Shimon Sakaguchi, Mitchell Kronenberg, Tony Tiganis, Michel L. Tremblay & 3 others Ferhat Ay, Pandurangan Vijayanand, Nunzio Bottini

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.

Original languageEnglish
Pages (from-to)1193-1210
Number of pages18
JournalThe Journal of clinical investigation
Volume129
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Autoimmune diseases
  • Autoimmunity
  • Immunology
  • Rheumatology
  • T cells

Cite this

Svensson, M. N., Doody, K. M., Schmiedel, B. J., Bhattacharyya, S., Panwar, B., Wiede, F., ... Bottini, N. (2019). Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. The Journal of clinical investigation, 129(3), 1193-1210. https://doi.org/10.1172/JCI123267
Svensson, Mattias Nd ; Doody, Karen M. ; Schmiedel, Benjamin J. ; Bhattacharyya, Sourya ; Panwar, Bharat ; Wiede, Florian ; Yang, Shen ; Santelli, Eugenio ; Wu, Dennis J. ; Sacchetti, Cristiano ; Gujar, Ravindra ; Seumois, Gregory ; Kiosses, William B. ; Aubry, Isabelle ; Kim, Gisen ; Mydel, Piotr ; Sakaguchi, Shimon ; Kronenberg, Mitchell ; Tiganis, Tony ; Tremblay, Michel L. ; Ay, Ferhat ; Vijayanand, Pandurangan ; Bottini, Nunzio. / Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. In: The Journal of clinical investigation. 2019 ; Vol. 129, No. 3. pp. 1193-1210.
@article{7f5860eb74cd41f2974c1050fcc6812d,
title = "Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity",
abstract = "Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.",
keywords = "Autoimmune diseases, Autoimmunity, Immunology, Rheumatology, T cells",
author = "Svensson, {Mattias Nd} and Doody, {Karen M.} and Schmiedel, {Benjamin J.} and Sourya Bhattacharyya and Bharat Panwar and Florian Wiede and Shen Yang and Eugenio Santelli and Wu, {Dennis J.} and Cristiano Sacchetti and Ravindra Gujar and Gregory Seumois and Kiosses, {William B.} and Isabelle Aubry and Gisen Kim and Piotr Mydel and Shimon Sakaguchi and Mitchell Kronenberg and Tony Tiganis and Tremblay, {Michel L.} and Ferhat Ay and Pandurangan Vijayanand and Nunzio Bottini",
year = "2019",
month = "3",
day = "1",
doi = "10.1172/JCI123267",
language = "English",
volume = "129",
pages = "1193--1210",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "3",

}

Svensson, MN, Doody, KM, Schmiedel, BJ, Bhattacharyya, S, Panwar, B, Wiede, F, Yang, S, Santelli, E, Wu, DJ, Sacchetti, C, Gujar, R, Seumois, G, Kiosses, WB, Aubry, I, Kim, G, Mydel, P, Sakaguchi, S, Kronenberg, M, Tiganis, T, Tremblay, ML, Ay, F, Vijayanand, P & Bottini, N 2019, 'Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity', The Journal of clinical investigation, vol. 129, no. 3, pp. 1193-1210. https://doi.org/10.1172/JCI123267

Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. / Svensson, Mattias Nd; Doody, Karen M.; Schmiedel, Benjamin J.; Bhattacharyya, Sourya; Panwar, Bharat; Wiede, Florian; Yang, Shen; Santelli, Eugenio; Wu, Dennis J.; Sacchetti, Cristiano; Gujar, Ravindra; Seumois, Gregory; Kiosses, William B.; Aubry, Isabelle; Kim, Gisen; Mydel, Piotr; Sakaguchi, Shimon; Kronenberg, Mitchell; Tiganis, Tony; Tremblay, Michel L.; Ay, Ferhat; Vijayanand, Pandurangan; Bottini, Nunzio.

In: The Journal of clinical investigation, Vol. 129, No. 3, 01.03.2019, p. 1193-1210.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity

AU - Svensson, Mattias Nd

AU - Doody, Karen M.

AU - Schmiedel, Benjamin J.

AU - Bhattacharyya, Sourya

AU - Panwar, Bharat

AU - Wiede, Florian

AU - Yang, Shen

AU - Santelli, Eugenio

AU - Wu, Dennis J.

AU - Sacchetti, Cristiano

AU - Gujar, Ravindra

AU - Seumois, Gregory

AU - Kiosses, William B.

AU - Aubry, Isabelle

AU - Kim, Gisen

AU - Mydel, Piotr

AU - Sakaguchi, Shimon

AU - Kronenberg, Mitchell

AU - Tiganis, Tony

AU - Tremblay, Michel L.

AU - Ay, Ferhat

AU - Vijayanand, Pandurangan

AU - Bottini, Nunzio

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.

AB - Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.

KW - Autoimmune diseases

KW - Autoimmunity

KW - Immunology

KW - Rheumatology

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=85060534082&partnerID=8YFLogxK

U2 - 10.1172/JCI123267

DO - 10.1172/JCI123267

M3 - Article

VL - 129

SP - 1193

EP - 1210

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -