Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

作者：Yeh Li Tzu; Miaw Shi Chuen; Lin Ming Hong; Chou Feng Cheng; Shieh Shing Jia; Chuang Yi Ping; Lin Shih Hua; Chang Deh Ming; Sytwu Huey Kang^*

来源：The Journal of Immunology, 2013, 191(2): 594-607.

DOI：10.4049/jimmunol.1203380

Ptpn22 encodes PEST domain-enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (T-regs). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-gamma-producing T cells, and an increased ratio of CD4(+)Foxp(3+) T-regs to CD4(+)IFN-gamma(+) or to CD8(+)IFN-gamma(+) T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of T-regs or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4(+) T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag-driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling-mediated functions in diabetogenic T cells but not in T-regs.

• 出版日期2013-7-15
• 单位河北医科大学