GSE123484
Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [RNA-seq]
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 (Treg) plays a role in autoimmunity. Here we  show that a reduction in Ptpn2 expression, comparable to that reported in human  carriers of autoimmune-predisposing PTPN2 variants, unexpectedly enhances the  severity of autoimmune arthritis 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 RORgt 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 RORgt+ Treg and that loss of function of PTPN2 in Treg contributes to the association between PTPN2 and autoimmunity. Overall design: Gene expression analysis by RNA-Sequencing of Tregs and exTregs isolated during arthritis development in mice or after in vitro culutre.