Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.
Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.
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DOI：
10.1371/journal.ppat.1006401
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发表时间：
2017-05
期刊：
影响因子：
6.7
通讯作者：
Ghiasi H
中科院分区：
文献类型：
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作者：
Lee DH;Zandian M;Kuo J;Mott KR;Chen S;Arditi M;Ghiasi H
我们已经建立了两种中枢神经系统（CNS）脱髓鞘的小鼠模型，其不同于大多数其他可用的多发性硬化症（MS）模型，因为它们代表了病毒和免疫触发剂的混合物。在第一个模型中，用组成型表达鼠IL-2的重组HSV-1（HSV-IL-2）对不同品系的小鼠进行眼部感染，导致CNS脱髓鞘。在第二种模型中，巨噬细胞的消耗导致眼部感染野生型（WT）HSV-1的小鼠的CNS脱髓鞘。在本研究中，我们发现，在巨噬细胞完整的小鼠感染HSV-IL-2的脱髓鞘被阻断的FoxP 3表达细胞的耗竭，而同时耗竭的巨噬细胞恢复脱髓鞘。相反，在用野生型HSV-1感染的巨噬细胞耗竭小鼠中，在表达FoxP 3的细胞耗竭后，脱髓鞘被阻断。在巨噬细胞耗竭的HSV-IL-2感染小鼠中，脱髓鞘与CD 4+和CD 8 + T细胞的活性相关，而在巨噬细胞耗竭的WT HSV-1感染小鼠中，脱髓鞘与CD 4 + T细胞相关。巨噬细胞耗竭或感染HSV-IL-2引起T细胞和TH 1应答的失衡以及IL-12 p35和IL-12 p40的改变，但不引起IL-12家族的其他成员或其受体的改变。脱髓鞘被HSV-IL-12 p70或HSV-IL-12 p40感染但不被HSV-IL-12 p35感染的巨噬细胞的过继转移阻断。这些结果表明，通过IL-2抑制IL-12 p70形成或在巨噬细胞耗竭后引起T细胞自身反应性，导致HSV-1感染小鼠的CNS脱髓鞘。现在有几种多发性硬化症（MS）的小鼠模型。我们建立了两种新的小鼠模型。在第一个模型中，用HSV-IL-2重组病毒眼部感染不同品系的小鼠导致CNS脱髓鞘。在第二个模型中，CNS脱髓鞘是由不同株的野生型HSV-1在巨噬细胞的情况下诱导的。在本研究中，我们发现两种模型中T细胞反应性的差异。然而，两种模型均表现出IL-12 p35和IL-12 p40的不平衡。过继转移实验支持在预防脱髓鞘中形成IL-12 p70二聚体的需要。这些结果表明巨噬细胞在这些病毒诱导的MS模型中的病理作用，其中通过IL-2或在巨噬细胞耗竭后抑制IL-12 p70形成引起T细胞自身反应性，导致CNS脱髓鞘。
We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice. Several mouse models of multiple sclerosis (MS) are now available. We have established two new mouse models. In the first model, ocular infection of different strains of mice with HSV-IL-2 recombinant virus causes CNS demyelination. In the second model, CNS demyelination was induced by different strains of wild type HSV-1 in the absence of macrophages. In the present study, we found differences in T-cell reactivity in the two models. However, both models exhibited an imbalance in IL-12p35 and IL-12p40. The requirement for formation of the IL-12p70 dimer in prevention of demyelination was supported by adoptive transfer experiments. These results suggest a pathological role for macrophages in these models of virus-induced MS in which suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination.