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 1

RA-associated haploinsufficiency of Ptpn2 promotes T cell–dependent arthritis in mice.

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RA-associated haploinsufficiency of Ptpn2 promotes T cell–dependent arth...
(A) UCSC tracks showing the chromosomal location of the human PTPN2 gene, containing a large haplotype block of RA-associated SNPs. Black lines indicate SNPs’ genomic location (the characterizing SNPs rs2847297, rs1893217, and rs8083786 are indicated in red), and DNase hypersensitivity sites (DHSs). Example tracks of H3K4me1-seq from CD4+ T cells, CD19+ B cells, CD14+ monocytes, and heart tissue. RPKM, reads per kilobase of transcript per million mapped reads. (B) Number of DHSs in the PTPN2 locus in single data sets of 4 primary cell types. (C) Heatmap of RA-associated SNPs (columns) that overlap with DHSs in different primary cell types (rows). (D) Development of K/BxN serum-induced arthritis in Ptpn2+/+ (n = 9) and Ptpn2+/– (n = 7) male BALB/c mice. (E) Clinical score and ankle thickness during development of spontaneous arthritis in female Ptpn2+/+ (n = 8) and Ptpn2+/– (n = 8) SKG mice. Compiled data from at least 2 independent experiments are shown in D and E. Arthritis severity was quantified using the area under the curve. Bars represent mean ± SEM. **P < 0.01, ***P < 0.001 by Mann-Whitney.