Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells.
Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells.
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DOI：
10.1084/jem.20020383
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发表时间：
2003-02-17
期刊：
影响因子：
--
通讯作者：
Goronzy JJ
中科院分区：
文献类型：
--
作者：
Snyder MR;Lucas M;Vivier E;Weyand CM;Goronzy JJ
CD 4 + T细胞的活化受刺激性和抑制性受体之间的相互作用控制;刺激性信号的优势有利于自身免疫反应。在类风湿性关节炎患者中，关键的共刺激分子CD 28的表达经常丢失。相反，CD 4 + CD 28 null T细胞表达杀伤免疫球蛋白样受体（KIR），优先表达刺激性受体CD 158 j。类风湿性关节炎（RA）患者中CD 4 + CD 28 null T细胞的频率与更严重疾病的风险相关。此外，编码CD 158 j的KIR 2DS 2基因是类风湿性血管炎的遗传风险因素。CD 158 j通过衔接分子KARAP/DAP 12发出信号，以正向调节NK细胞中的细胞毒性活性。然而，大多数CD 4 + CD 28 null T细胞克隆缺乏KARAP/DAP 12的表达。尽管不存在KARAP/DAP 12，但CD 158 j在T细胞受体刺激后具有功能并增加干扰素-γ的产生。CD 158 j的交联导致c-Jun NH 2-末端蛋白激酶（JNK）及其上游激酶MKK 4的选择性磷酸化，其导致ATF-2和c-Jun的表达，所有这些都是在细胞外信号调节激酶（ERK）1/2磷酸化不存在的情况下。CD 158 j跨膜结构域内赖氨酸残基的突变消除了JNK活化，表明正在使用替代衔接分子。CD 4 + CD 28 null T细胞表达DAP 10，抑制DAP 10下游的磷脂酰肌醇3-激酶可抑制JNK活化;然而，未检测到DAP 10与CD 158 j的相互作用。我们的数据表明，CD 158 j在T细胞中作为一个共刺激分子通过JNK途径的KARAP/DAP 12和DAP 10独立的功能。CD 158 j的共刺激可能参与了RA中CD 4 + CD 28 null T细胞的自身反应性。
Activation of CD4+ T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4+CD28null T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4+CD28null T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4+CD28null T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-γ production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH2-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal–regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4+CD28null T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4+CD28null T cells in RA.
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