Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity.
Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity.
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DOI：
10.4049/jimmunol.0803557
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Bergmann CC
中科院分区：
文献类型：
--
作者：
Phares TW;Ramakrishna C;Parra GI;Epstein A;Chen L;Atkinson R;Stohlman SA;Bergmann CC
嗜神经冠状病毒JHMV持续存在于少突胶质细胞，尽管存在病毒特异性CD 8 T细胞。研究了急性和持续感染期间程序性死亡-1（PD-1）和B7-H1的表达，以检查这种负调节机制是否有助于中枢神经系统病毒的持续存在。大多数CNS浸润性CD 8 T细胞表达PD-1，在病毒特异性CD 8 T细胞上表达水平最高。此外，尽管控制了感染性病毒，但持续感染小鼠CNS内的CD 8 T细胞仍保持高PD-1表达。体内病毒易感靶细胞的分析显示，B7-H1表达以细胞类型依赖性方式调节。少突胶质细胞和小胶质细胞上调B7-H1感染后，然而，虽然B7-H1表达的少突胶质细胞是突出的和持续的，它是显着减少和短暂的小胶质细胞。IFN-γ或IFN-α/β受体缺陷小鼠感染表明，B7-H1在少突胶质细胞上的表达主要受IFN-γ调节。体外阻断B7-H1对少突胶质细胞的抗体增强病毒特异性CD 8 T细胞分泌IFN-γB7-H1缺陷小鼠CNS内更有效的病毒控制证实了体内CD 8 T细胞功能的抑制。然而，B7-H1的缺失显著增加了发病率，而没有改变脱髓鞘。这些数据首次证明了体内神经胶质细胞类型依赖性B7-H1调节，导致对抗病毒CD 8 T细胞功能的不利影响。然而，PD-1：B7-H1相互作用在限制发病率方面的有益作用突出了评估组织特异性干预策略的必要性。
The neurotropic coronavirus JHMV persists in oligodendroglia despite the presence of virus-specific CD8 T cells. Expression of programmed death-1 (PD-1) and B7-H1 were studied during acute and persistent infection to examine if this negative regulatory mechanism contributes to CNS viral persistence. The majority of CNS infiltrating CD8 T cells expressed PD-1, with highest levels on virus-specific CD8 T cells. Moreover, despite control of infectious virus, CD8 T cells within the CNS of persistently infected mice maintained high PD-1 expression. Analysis of virus susceptible target cells in vivo revealed that B7-H1 expression was regulated in a cell type dependent manner. Oligodendroglia and microglia up-regulated B7-H1 following infection; however, while B7-H1 expression on oligodendroglia was prominent and sustained, it was significantly reduced and transient on microglia. Infection of mice deficient in IFN-γ or IFN-α/β receptor demonstrated B7-H1 expression on oligodendroglia is predominantly regulated by IFN-γ. Antibody blockade of B7-H1 on oligodendroglia in vitro enhanced IFN-γ secretion by virus-specific CD8 T cells. More efficient virus control within the CNS of B7-H1 deficient mice confirmed inhibition of CD8 T cell function in vivo. Nevertheless, the absence of B7-H1 significantly increased morbidity without altering demyelination. These data are the first to demonstrate glia cell type dependent B7-H1 regulation in vivo, resulting in adverse effects on antiviral CD8 T cell function. However, the beneficial role of PD-1:B7-H1 interactions in limiting morbidity highlight the need to evaluate tissue specific intervention strategies.
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