CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis
CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis
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DOI：
10.1073/pnas.0711175105
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发表时间：
2008-07-08
影响因子：
11.1
通讯作者：
Bynoe, Margaret S.
中科院分区：
文献类型：
--
作者：
Mills, Jeffrey H.;Thompson, Linda F.;Bynoe, Margaret S.
CD 73是嘌呤分解代谢途径的细胞表面酶，催化AMP分解为腺苷。由于腺苷的强免疫抑制和免疫抑制特性，我们预测cd 73（-/-）小鼠将发展严重的实验性自身免疫性脑脊髓炎（EAE），一种中枢神经系统（CNS）炎性疾病多发性硬化症的动物模型。令人惊讶的是，cd 73（-/-）小鼠对EAE具有抗性。然而，来自cd 73（-/-）小鼠的CD 4 T细胞比野生型（WT）小鼠分泌更多的促炎细胞因子，并且当转移到初始cd 73（+/+）T细胞缺陷型受体中时能够诱导EAE。因此，在cd 73（-/-）小鼠中观察到的对EAE的保护不是由T细胞反应性缺陷引起的。免疫组织化学显示，与WT小鼠相比，cd 73（-/-）小鼠CNS中浸润的淋巴细胞较少。重要的是，在转移WT CD 73（+）CD 4（+）T细胞后，可在cd 73（-/-）小鼠中诱导对EAE的易感性，这表明CD 73必须在T细胞或CNS中表达以诱导疾病。在寻找可能促进淋巴细胞迁移的CNS中CD 73的来源时，免疫组织化学显示脑内皮细胞上缺乏CD 73表达，脉络丛上皮中高表达，脉络丛上皮调节血液和脑脊液之间的淋巴细胞免疫监视。由于阻断腺苷受体信号与A（2a）腺苷受体特异性拮抗剂SCH 58261保护WT小鼠从EAE诱导，我们得出结论，C673的表达和腺苷受体信号是必需的有效进入中枢神经系统的淋巴细胞在EAE的发展。
CD73 is a cell surface enzyme of the purine catabolic pathway that catalyzes the breakdown of AMP to adenosine. Because of the strong immunosuppressive and antiinflammatory properties of adenosine, we predicted that cd73(-/-) mice would develop severe experimental autoimmune encephalomyelitis (EAE), an animal model for the central nervous system (CNS) inflammatory disease, multiple sclerosis. Surprisingly, cd73(-/-) mice were resistant to EAE. However, CD4 T cells from cd73(-/-) mice secreted more proinflammatory cytokines than wild-type (WT) mice and were able to induce EAE when transferred into naive cd73(+/+) T cell-deficient recipients. Therefore, the protection from EAE observed in cd73(-/-) mice was not caused by a deficiency in T cell responsiveness. Immunohistochemistry showed that cd73(-/-) mice had fewer infiltrating lymphocytes in their CNS compared with WT mice. Importantly, susceptibility to EAE could be induced in cd73(-/-) mice after the transfer of WT CD73(+)CD4(+) T cells, suggesting that CD73 must be expressed either on T cells or in the CNS for disease induction. In the search for the source of CD73 in the CNS that might facilitate lymphocyte migration, immunohistochemistry revealed a lack of CD73 expression on brain endothelial cells and high expression in the choroid plexus epithelium which regulates lymphocyte immunosurveillance between the blood and cerebrospinal fluid. Because blockade of adenosine receptor signaling with the A(2a) adenosine receptor-specific antagonist SCH58261 protected WT mice from EAE induction, we conclude that C673 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS during EAE development.