IL-10-dependent suppression of experimental allergic encephalomyelitis by Th2-differentiated, anti-TCR redirected T lymphocytes
IL-10-dependent suppression of experimental allergic encephalomyelitis by Th2-differentiated, anti-TCR redirected T lymphocytes
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DOI：
10.4049/jimmunol.174.6.3789
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发表时间：
2005-03-15
影响因子：
4.4
通讯作者：
Geiger, TL
中科院分区：
文献类型：
--
作者：
Mekala, DJ;Alli, RS;Geiger, TL
我们先前表明，转基因表达的嵌合Ag-MHC-zeta受体可以Ag-特异性重定向T细胞对其他T细胞。当受体的细胞外Ag-MHC结构域与Ag特异性T细胞上的同源TCR接合时，其细胞质ζ链刺激嵌合受体修饰的T细胞（RMTC）。这诱导效应子功能，如细胞溶解和细胞因子释放。表达髓鞘碱性蛋白（MBP）89-101-IA（s）-ζ受体的RMTC可用于治疗性地、Ag特异性地治疗由MBP 89 -101特异性T细胞介导的鼠实验性变应性脑脊髓炎（EAE）。在最初的研究中，分离的CD 8（+）RMTC在治疗上有效，而CD 4（+）RNITC则无效。我们在这里重新检查CD 4（+）RMTC的治疗潜力。我们证明，Th 2分化的，虽然不是Th 1分化的，CD 4（+）MBP 89 -101-IA（s）-zeta RMTC预防主动诱导或过继转移的EAE，并治疗EAE，即使在病理性T细胞反应的抗原多样化后。Th 2 RMTC既能使自身反应性T细胞偏离Th 2，又能抑制自身抗原特异性T细胞增殖。IL-10对抑制作用至关重要。抗IL-10 R阻断RMTC介导的EAE调节和自身抗原增殖抑制，以及自身反应性T细胞诱导IL-10产生。与IL-10相反，IL-4是自身反应性T细胞产生IL-4所必需的，因此是Th 2偏离所必需的，但不是RMTC的治疗活性所必需的。因此，这些结果证明了用RMTC进行Ag特异性治疗自身免疫性疾病的新的免疫抑制方法。他们进一步确定了IL-10在这些重定向的Th 2 T细胞的治疗有效性中的重要作用，而不是Th 2偏离本身。
We previously showed that transgenically expressed chimeric Ag-MHC-zeta receptors can Ag-specifically redirect T cells against other T cells. When the receptor's extracellular Ag-MHC domain engages cognate TCR on an Ag-specific T cell, its cytoplasmic zeta-chain stimulates the chimeric receptor-modified T cell (RMTC). This induces effector functions such as cytolysis and cytokine release. RMTC expressing a myelin basic protein (MBP) 89-101-IA(s)-zeta receptor can be used therapeutically, Ag-specifically treating murine experimental allergic encephalomyelitis (EAE) mediated by MBP89-101-specific T cells. In initial studies, isolated CD8(+) RMTC were therapeutically effective whereas CD4(+) RNITC were not. We re-examine here the therapeutic potential of CD4(+) RMTC. We demonstrate that Th2-differentiated, though not Th1-differentiated, CD4(+) MBP89-101-IA(s)-zeta RMTC prevent actively induced or adoptively transferred EAE, and treat EAE even after antigenic diversification of the pathologic T cell response. The Th2 RMTC both Th2-deviate autoreactive T cells and suppress autoantigen-specific T cell proliferation. IL-10 is critical for the suppressive effects. Anti-IL-10R blocks RMTC-mediated modulation of EAE and suppression of autoantigen proliferation, as well as the induction of IL-10 production by autoreactive T cells. In contrast to IL-10, IL-4 is required for IL-4 production by, and hence Th2 deviation of autoreactive T cells, but not the therapeutic activity of the RMTC. These results therefore demonstrate a novel immunotherapeutic approach for the Ag-specific treatment of autoimmune disease with RMTC. They further identify an essential role for IL-10, rather than Th2-deviation itself, in the therapeutic effectiveness of these redirected Th2 T cells.