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J Clin Invest. 2019 Mar 1;129(3):1193-1210. doi: 10.1172/JCI123267. Epub 2019 Feb 11.

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

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Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Division of Cellular Biology, and.
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Core Microscopy, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Clinical Science, Broegelmann Research Laboratory, Bergen, Norway.
Department of Microbiology, Jagiellonian University, Krakow, Poland.
Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Monash Biomedicine Discovery Institute, and.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.


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.


Autoimmune diseases; Autoimmunity; Immunology; Rheumatology; T cells

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