T-Cell-specific PTPN2 deficiency in NOD mice accelerates the development of type 1 diabetes and autoimmune comorbidities

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.

Item ID: 59984
Item Type: Article (Research - C1)
ISSN: 1939-327X
Copyright Information: © 2019 by the American Diabetes Association.
Funders: National Health and Medical Research Council of Australia (NHMRC), Versus Arthritis (VA), Victorian Operational Infrastructure Support Program
Projects and Grants: NHMRC 1047055, VA 19796 & 20770, NHMRC Principal Research Fellow 1103037
Date Deposited: 05 Jun 2019 07:33
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 100%
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