Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease
Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease
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DOI：
10.1016/j.immuni.2004.06.020
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发表时间：
2004-09-01
期刊：
影响因子：
32.4
通讯作者：
Jabri, B
中科院分区：
文献类型：
--
作者：
Meresse, B;Chen, ZG;Jabri, B
NKG2D连接天然免疫和获得性免疫的一个主要功能是通过共激活TCR信号上调表达应激诱导的NKG2D配体(如MIC)的组织中抗原特异性CTL介导的细胞毒性。在此，我们证明，在乳糜泻患者体内和健康个体体外IL15表达异常的条件下，导致ERK和JNK激活的NKG2D/DAP10信号通路的多个步骤被协同启动，以激活效应CD8T细胞的直接细胞溶解功能，而不依赖TCR的特异性。这些发现不仅可以解释先前报道的在高剂量IL2(IL15的替代品)作用下CTL转化为NK样淋巴因子激活的杀伤细胞(LAK细胞)的报道，而且对认识和治疗免疫病理疾病也有重要意义。
A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.