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T Cell-Specific PTPN2-Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune Co-Morbidities.

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1251-1266
Number of pages16
JournalDiabetes
Volume68
Issue number6
Early online date20 May 2019
DOIs
DateAccepted/In press - 17 Mar 2019
DateE-pub ahead of print - 20 May 2019
DatePublished (current) - 1 Jun 2019

Abstract

Genome-wide association studies have identified PTPN2 as an important non-MHC gene for autoimmunity. Single nucleotide polymorphisms that reduce PTPN2 expression have been linked with the development of various autoimmune disorders, including type 1 diabetes. The tyrosine phosphatase PTPN2 attenuates T-cell receptor and cytokine signaling in T cells to maintain peripheral tolerance, but the extent to which PTPN2 deficiency in T cells might influence type 1 diabetes onset remains unclear. NOD mice develop spontaneous autoimmune type 1 diabetes similar to that seen in humans. In this study, T-cell PTPN2 deficiency in NOD mice markedly accelerated the onset and increased the incidence of type 1 diabetes as well as that of other disorders, including colitis and Sjögren syndrome. Although PTPN2 deficiency in CD8 + T cells alone was able to drive the destruction of pancreatic β-cells and the onset of diabetes, T-cell-specific PTPN2 deficiency was also accompanied by increased CD4 + T-helper type 1 differentiation and T-follicular-helper cell polarization and increased the abundance of B cells in pancreatic islets as seen in human type 1 diabetes. These findings causally link PTPN2 deficiency in T cells with the development of type 1 diabetes and associated autoimmune comorbidities.

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via American Diabetes Association at https://doi.org/10.2337/db18-1362 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 5 MB, PDF document

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