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 12

Increased conversion of Ptpn2-haploinsufficient Tregs is mediated through STAT3.

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Increased conversion of Ptpn2-haploinsufficient Tregs is mediated throug...
(A) Motif enrichment analysis on differentially accessible regions identified by pairwise comparison of Tregs 24h versus Tregs 48h (“Treg 48 h”), Tregs 48h versus Tregs 72h (“Treg 72 h”), and Tregs 72h versus exTregs 72h (“exTreg 72 h”). Arrows indicate transcription factors that have been reported to associate with STAT3 functions in CD4+ T cells. Motifs with an enrichment log P value less than –35 and found in 10% or more regions and a fold increase of 2.5 over background were used to generate the heatmap. Motif enrichment analysis performed on ATAC-Seq experiment in Figure 10. (B) Activation of STAT3 (pY705) induced by 5 ng/ml IL-6 in Ptpn2+/+ and Ptpn2+/– effector SKG Tregs, analyzed by flow cytometry. (C) In vitro conversion of Ptpn2fl/fl.Lck-Cre– (n = 5), Ptpn2fl/fl.Lck-Cre+ (n = 5), and Ptpn2fl/flStat3fl/+.Lck-Cre+ (n = 5) Tregs isolated from non-SKG B6 mice. Compiled data from 2 experiments are presented (B and C). Each symbol represents an individual mouse in B and C. Two independent replicates are used for ATAC-Seq heatmap. Bars represent mean ± SEM. *P < 0.05, **P < 0.01 by unpaired t test (B) or Mann-Whitney (C).