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Diabetes. 2019 Apr 1. pii: db181362. doi: 10.2337/db18-1362. [Epub ahead of print]

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

Wiede F1,2,3, Brodnicki T4,5, Goh PK6,2,3, Leong YA2, Jones GW7,8,9, Yu D2, Baxter AG10, Jones SA7,8, Kay T4,5, Tiganis T1,2,3.

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Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia,
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800.
Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
St. Vincent's Institute, Fitzroy, Victoria 3065, Australia.
Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria 3065, Australia.
Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK.
Systems Immunity University Research Institute, Cardiff University, Cardiff, Wales, UK.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia.


Genome-wide association studies have identified PTPN2 as an important non-major histocompatibility complex gene for autoimmunity. Single nucleotide polymorphisms that reduce PTPN2 expression have been linked with the development of varied autoimmune disorders, including type 1 diabetes. The tyrosine-phosphatase PTPN2 attenuates T cell receptor and cytokine signalling 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. Non-Obese Diabetic (NOD) mice develop spontaneous autoimmune type 1 diabetes, similar to that seen in humans. 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 Sjogren's syndrome. Although PTPN2-deficiency in CD8+ T cells alone was able to drive the destruction of pancreatic β cells and onset of diabetes, T cell-specific PTPN2-deficiency was also accompanied by increased CD4+ T-helper type 1 differentiation and T follicular helper cell polarisation and an increased 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 co-morbidities.


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