Zhao H, Yan M, Wang H, Erickson S, Grewal I S, Dixit V M
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
J Exp Med. 2001 Nov 19;194(10):1441-8. doi: 10.1084/jem.194.10.1441.
During an immune response naive T helper (Th) cells differentiate into two functionally distinct subsets, Th1 and Th2, based on their cytokine secretion profile and immunomodulatory function. c-Jun amino terminal kinase (JNK) regulates Th cell differentiation by activating a transcriptional program required for cytokine production. We have recently identified a TNFR superfamily death domain-containing molecule, death receptor (DR)6, which potently activates JNK. T cells from DR6-deficient mice are substantially impaired in JNK activation. When DR6(-/-) mice were challenged with protein antigen, their T cells hyperproliferate and display a profound polarization toward a Th2 response whereas Th1 differentiation is not equivalently affected. In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro. The phenotype seen in the DR6(-/)- mice is not due to the apoptotic pathway. Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response. This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.
在免疫应答过程中，初始T辅助（Th）细胞根据其细胞因子分泌谱和免疫调节功能分化为两个功能不同的亚群，即Th1和Th2。c-Jun氨基末端激酶（JNK）通过激活细胞因子产生所需的转录程序来调节Th细胞分化。我们最近鉴定出一种含肿瘤坏死因子受体（TNFR）超家族死亡结构域的分子——死亡受体（DR）6，它能有效激活JNK。来自DR6缺陷小鼠的T细胞在JNK激活方面存在严重缺陷。当用蛋白质抗原攻击DR6（-/-）小鼠时，它们的T细胞过度增殖，并表现出向Th2应答的显著极化，而Th1分化受到的影响相对较小。此外，DR6（-/-）T细胞在体外表现出对Th2分化的偏好。DR6（-/-）小鼠中出现的表型并非由凋亡途径所致。因此，DR6通过JNK发挥作用，而非通过凋亡，其功能是减弱Th2应答。这首次证明了DR6特别是一般的死亡受体在Th细胞激活和分化中的作用。
