A new mechanism of NK cell cytotoxicity activation: the CD40-CD40 ligand interaction.
A new mechanism of NK cell cytotoxicity activation: the CD40-CD40 ligand interaction.
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DOI：
10.1084/jem.185.12.2053
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发表时间：
1997-06-16
期刊：
影响因子：
--
通讯作者：
Zappacosta S
中科院分区：
文献类型：
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作者：
Carbone E;Ruggiero G;Terrazzano G;Palomba C;Manzo C;Fontana S;Spits H;Kärre K;Zappacosta S
NK识别受启动其效应子功能的正信号和阻止其进行细胞溶解的抑制信号之间的微妙平衡调节。目前对NK细胞中负责阳性信号传导的分子的了解有限。我们证明IL-2激活的人NK细胞可以表达CD 40配体（CD 40 L），并且靶细胞上的CD 40识别可以为这样的人NK细胞提供激活途径。在IL-2存在下培养18 h的表达CD 40 L的NK细胞系、克隆和PBL衍生的NK细胞可杀死CD 40转染的P815细胞，但不被CD 40 L阴性的新鲜NK细胞杀死。IL-2激活的NK细胞上的CD 40 L的交联诱导了CD 40阴性但表达Fc受体的P815细胞的重定向细胞溶解。人TAP缺陷型T2细胞的敏感性可被抗CD 40抗体以及TAP/MHC I类表达的重建阻断，表明NK活化的CD 40依赖性途径可被靶细胞上的MHC I类分子下调，至少部分下调。NK细胞对CD 40的识别在免疫调节以及针对B细胞恶性肿瘤的免疫应答中可能是重要的。
NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.