Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
J Immunol. 2013 Jul 15;191(2):594-607. doi: 10.4049/jimmunol.1203380. Epub 2013 Jun 10.
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-γ-producing T cells, and an increased ratio of CD4(+)Foxp3(+) T(regs)to CD4(+)IFN-γ(+) or to CD8(+)IFN-γ(+) 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).
Ptpn22 编码富含 PEST 结构域的酪氨酸磷酸酶（Pep），它负向调节 TCR 近端信号转导，与人多种自身免疫性疾病密切相关。由于 Pep 同时抑制效应 T 细胞和调节性 T 细胞（Tregs）的 TCR 介导的信号转导，因此 Pep 对免疫和耐受平衡的净效应尚不确定。在本研究中，我们构建了在 T 细胞中过表达 Pep 的转基因 NOD 小鼠。这些转基因小鼠自发性自身免疫性糖尿病的发生率显著降低，伴随胰岛中 IFN-γ 产生 T 细胞减少，CD4+Foxp3+Tregs 与 CD4+IFN-γ+或 CD8+IFN-γ+T 细胞的比例分别增加。转基因 T 细胞表现出明显降低的 TCR 介导的效应细胞反应，如增殖和 Th1 分化。相比之下，转基因 Pep 对 TCR 信号的抑制作用并不影响 Tregs 的分化或其抑制活性。过继转移实验表明，转基因脾细胞的致糖尿病能力减弱。为了进一步研究转基因 T 细胞的致病特征，我们构建了 Ptpn22/BDC2.5 双转基因小鼠，并发现胰腺淋巴结中 CD4+T 淋巴细胞中的 Pep 进一步增加时，其增殖和 Th1 分化减少，但腹股沟淋巴结中没有这种变化。这一发现表明，转基因 Pep 通过在胰岛抗原驱动的方式减弱 T 细胞功能。总之，我们的结果表明，T 细胞中 Pep 的过表达通过优先调节致糖尿病 T 细胞而不是 Tregs 的 TCR 信号转导介导的功能，从而减轻 NOD 小鼠的自身免疫性糖尿病。
