Christensen Jeanette E, Simonsen Stine, Fenger Christina, Sørensen Maria R, Moos Torben, Christensen Jan P, Finsen Bente, Thomsen Allan R
University of Copenhagen, Department of International Health, Immunology and Microbiology, Copenhagen, Denmark.
J Immunol. 2009 Jan 15;182(2):1079-87. doi: 10.4049/jimmunol.182.2.1079.
Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30-50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.
用淋巴细胞性脉络丛脑膜炎病毒（LCMV）对免疫功能正常的小鼠进行脑内接种，通常会导致致命的CD8 + T细胞介导的脑膜脑炎。然而，在CXCL10缺陷型小鼠中，病毒诱导的CD8 + T细胞在神经实质中的积累受损，只有30 - 50%的小鼠死于感染。在匹配的趋化因子受体CXCR3缺陷的小鼠中也得到了类似的结果。这些发现共同表明CXCL10在调节LCMV诱导的炎症过程的严重程度中起关键作用。因此，我们现在探讨调节LCMV感染小鼠中枢神经系统中CXCL10表达的机制。我们使用I型干扰素受体、II型干扰素受体或II型干扰素缺陷的小鼠，以及仅在驻留细胞或仅在骨髓来源细胞中表达CXCL10的骨髓嵌合体，分析了CXCL10的上游调节以及细胞来源。我们发现CXCL10的表达最初依赖于通过I型干扰素受体的信号传导，而后期表达和上调则需要募集的CD8 + T细胞产生的II型干扰素。在整个感染过程中，CXCL10的产生者仅为中枢神经系统的驻留细胞，星形胶质细胞是神经实质中的主要表达者，而不是小胶质细胞或募集的骨髓来源细胞类型。这些结果与一个模型一致，该模型表明中枢神经系统的驻留细胞与募集的病毒特异性T细胞之间存在双向相互作用，星形胶质细胞是局部抗病毒宿主反应的积极参与者。
