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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.

Author information

1
Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia, Tony.Tiganis@monash.edu Florian.Wiede@petermac.org.
2
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800.
3
Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
4
St. Vincent's Institute, Fitzroy, Victoria 3065, Australia.
5
Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria 3065, Australia.
6
Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
7
Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK.
8
Systems Immunity University Research Institute, Cardiff University, Cardiff, Wales, UK.
9
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
10
Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia.

Abstract

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.

PMID:
30936146
DOI:
10.2337/db18-1362

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