Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity
Mattias N.D. Svensson, … , Pandurangan Vijayanand, Nunzio Bottini
Mattias N.D. Svensson, … , Pandurangan Vijayanand, Nunzio Bottini
Published January 8, 2019
Citation Information: J Clin Invest. 2019;129(3):1193-1210. https://doi.org/10.1172/JCI123267.
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Research Article Autoimmunity Immunology

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.

Authors

Mattias N.D. 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, Ferhat Ay, Pandurangan Vijayanand, Nunzio Bottini

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Figure 13

PTPN2 directly interacts with and dephosphorylates STAT3.

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PTPN2 directly interacts with and dephosphorylates STAT3. (A) Immunoprec...
(A) Immunoprecipitation of STAT3 in in vitro–expanded Tregs (expanded with IL-2 and anti-CD3/CD28–coated beads) after stimulation with IL-6 (50 ng/ml) for 20 minutes. All samples shown were separated on the same gel. WCL, whole cell lysate. (B) Dephosphorylation of STAT3β pY705 after incubation with (+) or without (–) recombinant PTPN2. Samples were taken at 0, 1 hour 45 minutes, 3 hours 30 minutes, and 7 hours for analysis. All samples shown were separated on the same gel. (C) Substrate trapping of STAT3β pY705 by the PTPN2 mutant (D182A, Q260A). Unphosphorylated STAT3β was used as a negative control and does not bind PTPN2, as shown. Proteins were analyzed by SDS-PAGE and run on the same gel. (D) Schematic of proposed mechanism by which partial loss of function in PTPN2 in Tregs promotes STAT3-mediated loss of FoxP3 and generation of IL-17A–producing exTregs. Representative experiments out of 2 (A) and 3 (B and C) independent replicates are shown. See complete unedited blots in the supplemental material.