Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice
Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice
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DOI：
10.4049/jimmunol.179.2.869
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发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Matozaki, Takashi
中科院分区：
文献类型：
--
作者：
Tomizawa, Takeshi;Kaneko, Yuka;Matozaki, Takashi
含 Src 同源 2 结构域的蛋白酪氨酸磷酸酶 (SHP) 底物-1 (SHPS-1) 是一种跨膜蛋白，通过其胞质区域结合蛋白酪氨酸磷酸酶 SHP-1 和 SHP-2，并在 CD11c(+) 树突状细胞 (DC) 和巨噬细胞的表面表达。在这项研究中，我们发现，表达缺乏大部分细胞质区域的 SHPS-1 突变体的小鼠对源自髓磷脂少突胶质细胞糖蛋白 (MOG (35-55)) 的肽进行免疫反应，对实验性自身免疫性脑脊髓炎 (EAE) 具有抵抗力。与野生型细胞相比，来自免疫的 SHPS-1 突变小鼠的 T 细胞的 MOG (35-55) 诱导的增殖和 IFN-γ、IL-2 和 IL-17 的产生减少。突变小鼠的脾 DC 刺激同种异体 MLR 和启动 Ag 特异性 T 细胞的能力降低。突变小鼠 DC 产生的 IL-12 刺激和 TLR 依赖性细胞因子也受到损害。最后，SHPS-1 突变小鼠对 MOG (35-55) 特异性 T 细胞的过继转移对 EAE 的诱导具有抵抗力。这些结果表明 DC 上的 SHPS-1 对于初始 T 细胞的启动和 EAE 的发展至关重要。因此，SHPS-1 是中枢神经系统炎症性疾病和其他自身免疫性疾病的潜在治疗靶点。
Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of CD11c(+) dendritic cells (DCs) and macrophages. In this study, we show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein (MOG (35-55)). The MOG (35-55)-induced proliferation of, and production of IFN-gamma, IL-2, and IL-17, by T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. The abilities of splenic DCs from mutant mice to stimulate an allogenic MLR and to prime Ag-specific T cells were reduced. Both IL-12-stimulated and TLR-dependent cytokine production by DCs of mutant mice were also impaired. Finally, SHPS-1 mutant mice were resistant to induction of EAE by adoptive transfer of MOG (35-55)-specific T cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the CNS and other autoimmune diseases.