Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis.
Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis.
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DOI：
10.1084/jem.193.6.713
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发表时间：
2001-03-19
影响因子：
15.3
通讯作者：
Ransohoff, R M
中科院分区：
文献类型：
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作者：
Huang, D R;Wang, J;Kivisakk, P;Rollins, B J;Ransohoff, R M
单核细胞趋化蛋白(MCP)-1通过引导单核细胞向炎症部位迁移，在先天免疫中发挥重要作用。最近的数据表明，这种趋化因子在适应性免疫中作为T细胞对辅助性T细胞2型(Th2)效应器功能的调节而发挥作用。在Th1依赖的动物模型-实验性自身免疫性脑脊髓炎(EAE)中的研究表明，MCP-1在受影响的啮齿动物的中枢神经系统(CNS)中高表达，MCP-1抗体可以阻止疾病的复发。缺乏主要MCP-1受体CC趋化因子受体(CCR)2的小鼠在主动免疫后不会发生EAE，但会产生效应细胞，将疾病传播给幼稚的野生型接受者。我们分析了缺乏MCP-1的小鼠的EAE，以确定CCR2的相关配体，CCR2对小鼠的MCP-1、MCP-2、MCP-3和MCP-5有反应。我们发现C57BL/6 MCP-1基因缺失的小鼠在主动免疫后对EAE具有明显的抵抗力，巨噬细胞向中枢神经系统的募集严重受损，但仍能产生效应性T细胞，将严重疾病传播给幼稚的野生型受体。相比之下，将野生型小鼠的预置T细胞过继转移到MCP-1缺失的幼稚受者体内并不能调解临床上的EAE。在SJL的背景下，MCP-1基因的破坏产生了一种较温和的EAE表型，并减少了复发，这与以前使用抗MCP-1抗体的发现相似。在MCP-1缺失的EAE小鼠中，MCP-2、MCP-3和MCP-5的表达没有代偿性上调。这些结果表明，MCP-1是EAE小鼠的主要CCR2配体，为明确MCP-1在EAE中的作用提供了机会。与野生型相比，mcp-1−/−小鼠引流淋巴结和中枢神经系统中干扰素γ的表达减少，抗原特异性免疫球蛋白G1抗体的产生增加。综上所述，这些数据表明，MCP-1在EAE诱导的Th1免疫反应中至关重要，巨噬细胞需要募集到炎症的CNS靶器官，才能启动T细胞在EAE中执行Th1效应程序。
Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate immunity by directing the migration of monocytes into inflammatory sites. Recent data indicated a function for this chemokine in adaptive immunity as a regulator of T cell commitment to T helper cell type 2 (Th2) effector function. Studies in a Th1-dependent animal model, experimental autoimmune encephalomyelitis (EAE), showed that MCP-1 was highly expressed in the central nervous system (CNS) of affected rodents, and MCP-1 antibodies could block relapses of the disease. Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relevant ligand for CCR2, which responds to murine MCP-1, MCP-2, MCP-3, and MCP-5. We found that C57BL/6 MCP-1–null mice were markedly resistant to EAE after active immunization, with drastically impaired recruitment of macrophages to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of primed T cells from wild-type mice into naive MCP-1–null recipients did not mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked previous findings using anti–MCP-1 antibodies. There was no compensatory upregulation of MCP-2, MCP-3, or MCP-5 in MCP-1–null mice with EAE. These results indicated that MCP-1 is the major CCR2 ligand in mice with EAE, and provided an opportunity to define the role of MCP-1 in EAE. Compared with wild-type littermates, MCP-1−/− mice exhibited reduced expression of interferon γ in draining lymph node and CNS and increased antigen-specific immunoglobulin G1 antibody production. Taken together, these data demonstrate that MCP-1 is crucial for Th1 immune responses in EAE induction and that macrophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE.