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

Mattias Nd 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. TremblayFerhat Ay, Pandurangan Vijayanand, Nunzio Bottini

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13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1193-1210
Number of pages18
JournalJournal of Clinical Investigation
Volume129
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Autoimmune diseases
  • Autoimmunity
  • Immunology
  • Rheumatology
  • T cells

Cite this

Svensson, M. N., Doody, K. M., Schmiedel, B. J., Bhattacharyya, S., Panwar, B., Wiede, F., Yang, S., Santelli, E., Wu, D. J., Sacchetti, C., Gujar, R., Seumois, G., Kiosses, W. B., Aubry, I., Kim, G., Mydel, P., Sakaguchi, S., Kronenberg, M., Tiganis, T., ... Bottini, N. (2019). Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. Journal of Clinical Investigation, 129(3), 1193-1210. https://doi.org/10.1172/JCI123267