Wiede, Florian, Brodnicki, Thomas C., Goh, Pei Kee, Leong, Yew A., Jones, Gareth W., Yu, Di, Baxter, Alan G., Jones, Simon A., Kay, Thomas W.H., and Tiganis, Tony (2019) T-Cell-specific PTPN2 deficiency in NOD mice accelerates the development of type 1 diabetes and autoimmune comorbidities. Diabetes, 68 (6). pp. 1251-1266.

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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 Sjogren syndrome. Although PTPN2 deficiency in CD8(+) T cells alone was able to drive the destruction of pancreatic beta-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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