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Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity
- Source :
- Journal of Clinical Investigation. March, 2019, Vol. 129 Issue 3, p1193, 18 p.
- Publication Year :
- 2019
-
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.sup.- ]driven autoimmunity. However, it remains unknown whether loss of PTPN2 in [FoxP3.sup.+] 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 ROR[gamma]t expression, at a stage when chromatin accessibility for STAT3-targeted [IL-17.sup.-]associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse [ROR[gamma]t.sup.+] Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.<br />Introduction Rheumatoid arthritis (RA) is a chronic autoimmune, systemic inflammatory disorder that primarily affects diarthrodial joints (1). To date, various genome-wide association studies have identified over 100 risk loci for [...]
- Subjects :
- Autoimmunity -- Research
Gene expression -- Research
Phosphatases -- Research
Rheumatoid arthritis -- Genetic aspects
T cells -- Research
DNA binding proteins
Rheumatoid factor
Arthritis
Phenols (Class of compounds)
Cytokines
B cells
Tyrosine
Chromatin
Autoimmune diseases
Genes
Biochemistry
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 129
- Issue :
- 3
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.577907803
- Full Text :
- https://doi.org/10.1172/JCI123267