CNS expression of B7-H1 regulates pro-inflammatory cytokine production and alters severity of Theiler's virus-induced demyelinating disease.
CNS expression of B7-H1 regulates pro-inflammatory cytokine production and alters severity of Theiler's virus-induced demyelinating disease.
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DOI：
10.1371/journal.pone.0018548
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发表时间：
2011-04-08
期刊：
影响因子：
3.7
通讯作者：
Miller SD
中科院分区：
文献类型：
--
作者：
Duncan DS;Miller SD
由于免疫监视能力有限，中枢神经系统是一个独特的器官。作为中枢神经系统的巨噬细胞，小胶质细胞最初以协助神经元稳定的能力而闻名，现在因其在启动和调节大脑免疫反应中的作用而受到赞赏。泰勒氏鼠脑脊髓炎病毒 (TMEV) 诱导的脱髓鞘疾病是多发性硬化症 (MS) 的小鼠模型。在体外响应 TMEV 感染时，小胶质细胞产生高水平的炎性细胞因子和趋化因子，并且是激活 CD4+ T 细胞的有效抗原呈递细胞 (APC)。然而，小胶质细胞和其他 CNS 浸润 APC 在体内响应 TMEV 的调节功能仍不清楚。在这里，我们证明小胶质细胞会增加增殖细胞核抗原（PCNA）的表达，并在表型上表达高水平的主要组织相容性复合体（MHC）-I类和II类，以响应SJL/J小鼠中TMEV的急性感染。小胶质细胞早在感染后第 5 天就增加了抑制性共刺激分子 B7-H1 的表达，而中枢神经系统浸润的 CD11b+CD11c−CD45HIGH 单核细胞/巨噬细胞和 CD11b+CD11c+CD45HIGH 树突状细胞在感染后第 3 天上调 B7-H1 的表达。利用中和抗体，我们证明 B7-H1 负调节 TMEV 特异性体外从 CD4+ 和 CD8+ T 细胞产生干扰素 (IFN)-γ、白细胞介素 (IL)-17、IL-10 和 IL-2。在 SJL/J 小鼠中体内阻断 B7-H1 会显着加剧 TMEV-IDD 慢性自身免疫阶段的临床疾病症状，但对病毒清除的影响很小。总的来说，这些结果表明 B7-H1 的 CNS 表达调节 TMEV 特异性 T 细胞的激活，从而影响对 TMEV-IDD 的保护。
The CNS is a unique organ due to its limited capacity for immune surveillance. As macrophages of the CNS, microglia represent a population originally known for the ability to assist neuronal stability, are now appreciated for their role in initiating and regulating immune responses in the brain. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a mouse model of multiple sclerosis (MS). In response to TMEV infection in vitro, microglia produce high levels of inflammatory cytokines and chemokines, and are efficient antigen-presenting cells (APCs) for activating CD4+ T cells. However, the regulatory function of microglia and other CNS-infiltrating APCs in response to TMEV in vivo remains unclear. Here we demonstrate that microglia increase expression of proliferating cell nuclear antigen (PCNA), and phenotypically express high levels of major histocompatibility complex (MHC)-Class I and II in response to acute infection with TMEV in SJL/J mice. Microglia increase expression of the inhibitory co-stimulatory molecule, B7-H1 as early as day 5 post-infection, while CNS-infiltrating CD11b+CD11c−CD45HIGH monocytes/macrophages and CD11b+CD11c+CD45HIGH dendritic cells upregulate expression of B7-H1 by day 3 post-infection. Utilizing a neutralizing antibody, we demonstrate that B7-H1 negatively regulates TMEV-specific ex vivo production of interferon (IFN)-γ, interleukin (IL)-17, IL-10, and IL-2 from CD4+ and CD8+ T cells. In vivo blockade of B7-H1 in SJL/J mice significantly exacerbates clinical disease symptoms during the chronic autoimmune stage of TMEV-IDD, but only has minimal effects on viral clearance. Collectively, these results suggest that CNS expression of B7-H1 regulates activation of TMEV-specific T cells, which affects protection against TMEV-IDD.
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DOI：
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发表时间：
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期刊：
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影响因子：
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