Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice
Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice
复制标题
DOI：
10.4049/jimmunol.175.3.1767
复制
发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Thomsen, AR
中科院分区：
文献类型：
--
作者：
de Lemos, C;Christensen, JE;Thomsen, AR
T细胞在中枢神经系统病毒感染的控制中起着关键作用，但也可能对免疫介导的细胞损伤起作用。为了研究趋化因子受体CXCR3和CCR5在调节病毒诱导的CD8(+)T细胞介导的脑内炎症中的冗余性，建立了CXCR3/CCR5双缺陷小鼠，并将其脑内感染非细胞溶血性淋巴细胞性脉络膜脑膜炎病毒。由于这些趋化因子受体主要是通过激活的CD8+T细胞的重叠亚群表达的，因此预计这两种受体的缺失将协同地削弱效应T细胞的侵袭，从而保护小鼠免受否则致命的CD8(+)T细胞介导的免疫攻击。与预期相反，与两种受体表达正常的小鼠相比，脑脊液中单个核细胞的积聚仅略有延迟。更令人惊讶的是，CXCR3/CCR5双缺陷小鼠比CXCR3缺陷小鼠更容易受到脑内感染。效应性T细胞生成分析显示，在CXCR3/CCR5双缺陷小鼠中，CD8(+)T细胞反应加速。此外，虽然CXCR3-和CXCR3/CCR5缺陷小鼠神经实质中CD8(+)T细胞的积累明显延迟，但当在临床结果明显不同的时候进行分析时，在双缺陷小鼠的神经实质中发现更多的CD8(+)T细胞。综上所述，这些结果表明，虽然CXCR3在控制中枢神经系统炎症方面发挥了重要作用，但其他受体也起到了重要作用，而不是CCR5。此外，我们的结果表明，CCR5主要作为抗病毒CD8(+)T细胞反应的负调节因子发挥作用。
T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8(+) T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice were generated and infected intracerebrally with noncytolytic lymphocytic choriomeningitis virus. Because these chemokine receptors are mostly expressed by overlapping subsets of activated CD8+ T cells, it was expected that absence of both receptors would synergistically impair effector T cell invasion and therefore protect mice against the otherwise fatal CD8(+) T cell-mediated immune attack. Contrary to expectations, the accumulation of mononuclear cells in cerebrospinal fluid was only slightly delayed compared with mice with normal expression of both receptors. Even more surprising, CXCR3/CCR5 double-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8(+) T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8(+) T cells in the neural parenchyma was significantly delayed in both CXCR3- and CXCR3/CCR5-deficient mice, more CD8(+) T cells were found in the parenchyma of double-deficient mice when these were analyzed around the time when the difference in clinical outcome becomes manifest. Taken together, these results indicate that while CXCR3 plays an important role in controlling CNS inflammation, other receptors but not CCR5 also contribute significantly. Additionally, our results suggest that CCR5 primarily functions as a negative regulator of the antiviral CD8(+) T cell response.