Cellular FLIP (Long Isoform) Overexpression in T Cells Drives Th2 Effector Responses and Promotes Immunoregulation in Experimental Autoimmune Encephalomyelitis1
Cellular FLIP (Long Isoform) Overexpression in T Cells Drives Th2 Effector Responses and Promotes Immunoregulation in Experimental Autoimmune Encephalomyelitis1
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T 细胞中的细胞 FLIP（长异构体）过度表达可驱动 Th2 效应器反应并促进实验性自身免疫性脑脊髓炎的免疫调节1
DOI：
10.4049/jimmunol.173.11.6619
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
L. Probert
中科院分区：
文献类型：
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作者：
V. Tseveleki;J. Bauer;E. Taoufik;Chengmai Ruan;L. Leondiadis;S. Haralambous;H. Lassmann;L. Probert
细胞翻转（c-FLIP）是一种内源性的死亡受体通过caspase 8途径诱导细胞凋亡的抑制剂。它是一种NF-κ b诱导的蛋白，被认为可以促进T细胞活化后的存活，其下调与活化诱导的细胞死亡有关。我们利用CD2启动子（TgFLIPL）在T细胞中产生了过表达人c-FLIP长型（c-FLIPL）的转基因小鼠。TgFLIPL小鼠在T细胞依赖性Ag的刺激下，IgG1的产生增加，对过敏原的接触超敏反应明显增强。除了表现出增强的th2型应答外，TgFLIPL小鼠对髓鞘少突胶质细胞糖蛋白35-55肽诱导的实验性自身免疫性脑脊髓炎（一种th1驱动的自身免疫性疾病）的发展具有抗性。体外分析显示，TgFLIPL小鼠的T细胞增殖正常，但产生更高水平的IL-2，并在抗原刺激下表现出Th2细胞因子产生细胞的优先成熟。过继性转移后，这些（Th2）细胞保护野生型受体小鼠免受实验性自身免疫性脑脊髓炎的诱导。我们的研究结果表明，c-FLIPL在T细胞中的组成性过表达足以驱动效应T细胞的Th2极化反应，并表明它可能是Th细胞分化的关键调节因子。
Cellular FLIP (c-FLIP) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase 8 pathway. It is an NF-κB-inducible protein thought to promote the survival of T cells upon activation, and its down-regulation has been implicated in activation-induced cell death. We have generated transgenic mice overexpressing human c-FLIP long form (c-FLIPL) specifically in T cells using the CD2 promoter (TgFLIPL). TgFLIPL mice exhibit increased IgG1 production upon stimulation by a T cell-dependent Ag and a markedly enhanced contact hypersensitivity response to allergen. In addition to showing augmented Th2-type responses, TgFLIPL mice are resistant to the development of myelin oligodendrocyte glycoprotein 35–55 peptide-induced experimental autoimmune encephalomyelitis, a Th1-driven autoimmune disease. In vitro analyses revealed that T cells of TgFLIPL mice proliferate normally, but produce higher levels of IL-2 and show preferential maturation of Th2 cytokine-producing cells in response to antigenic stimulation. After adoptive transfer, these (Th2) cells protected wild-type recipient mice from experimental autoimmune encephalomyelitis induction. Our results show that the constitutive overexpression of c-FLIPL in T cells is sufficient to drive Th2 polarization of effector T cell responses and indicate that it might function as a key regulator of Th cell differentiation.