Natural killing: An unexpected petition for pardon
Natural killing: An unexpected petition for pardon
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DOI：
10.1016/0960-9822(92)90179-e
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发表时间：
1992-01-01
期刊：
影响因子：
9.2
通讯作者：
Karre, Klas
中科院分区：
文献类型：
--
作者：
Karre, Klas
免疫系统必须能够区分朋友和敌人--这通常需要区分自我和非我。原则上，这种辨别可以通过承认存在意想不到的非我分子或不存在预期的自体分子来完成。B细胞和I细胞使用第一种策略，分别通过它们的免疫球蛋白和T细胞受体识别外来抗原。TH.神秘的自然杀伤细胞(NK细胞)，在20世纪70年代中期被发现[L]，但仍然鲜为人知，在我们看来，似乎是第二种策略。NK细胞识别和排斥从其他个体移植的肿瘤细胞、病毒感染细胞和造血细胞，但它们是如何做到这一点的尚不清楚。根据缺失自我模型[2，31，NK细胞是由其靶细胞中缺少某些主要组织相容性复合体(MHC)I类分子而触发的。混合I类分子由一个高度多态的重链、轻链J32-微球蛋白和一个紧密结合在重链m1/a2区形成的抗原结合槽中的多肽组成。MHC I类分子呈递的多肽抗原大多来自自身蛋白，但在感染细胞、肿瘤细胞或同种异体细胞中也包括“意想不到的COM”。脑桥，被T细胞识别为非我。这种抗原呈递系统的一个后果是，扰乱混合产物表达的突变或感染剂阻止多肽抗原暴露在细胞表面，从而使异常细胞逃脱免疫检测。然而，根据缺失自我模型，这样的细胞反而会落入NK识别的陷阱，就像确实表达混合I类分子的同种异体细胞一样，但表达错误的分子。NK细胞用来监测MHC I类分子缺失的受体一直不清楚，这是失踪自我模型所需的。目前也不清楚是否存在针对不同MHC基因产物的NK细胞亚群，如果存在，如何确定特异性以防止自身反应。然而，在解决这些问题方面正在取得进展：Karlhofer等人最近的一篇论文([4]，另见[51])报告了可能是混合I类分子的NK受体的鉴定；对人类NK细胞的研究开始揭示其识别机制[Gs]。~-49最初被鉴定为EL-4细胞表面的一种抗原，由单抗Al[9]识别。Ly-49基因已被克隆，该蛋白由两个45-50kD亚基组成[9-111]。它是一种带有细胞外C末端结构域的II型糖蛋白，表达于B6品系Karlhofer et AZ小鼠的一小部分脾细胞上。通过观察Ly-49的编码来研究它在m细胞特异性中的可能参与
The immune system must be able to tell friend from enemy-which generally entails distinguishing self from non-self. Such discrimination can in principle be done by recognizing either the presence of unexpected, non-self molecules or the absence of expected, self molecules. B cells and ‘I cells use the first strategy, and recognize foreign antigens with their immunoglobulins and T-cell receptors, respectively. Th. e enigmatic Natural Killer (NK) cells, discovered in the mid-1970s [l] but still poorly understood, seem to us’e the second strategy. NK cells recognize and reject tumor cells, virus-infected cells and hematopoietic cells transplanted from other individuals, but how they do this is unclear. According to the ‘missing self model [2, 31, NK cells are triggered by the absence from their target cells of certain major histocompatibility complex (MHC) class I molecules. MIX class I molecules consist of a highly polymorphic heavy chain, the light chain j3 2-microglobulin and a peptide tightly bound in the antigenbinding groove formed by the ml/a2 domains of the heavy chain. The peptide antigens presented by MHC class I molecules are mostly derived from self proteins, but in infected, neoplastic or allogeneic cells they also include ‘unexpected com. ponents, recognized as non-self by T cells. One consequence of this antigen presentation system is that mutations or infectious agents that perturb the expression of MIX products prevent peptide antigens from being exposed at the cell surface, thereby allowing abnormal cells to escape from immune detection. According to the missing self model, however, such cells would instead fall into the trap of NK recognition, as would allogeneic cells that do express MIX class I molecules, but the wrong ones. The receptors by which NK cells monitor the absence of MHC class I molecules, required by the missing self model, have been obscure. Nor has it been clear whether subsets of NK cells exist that are specific for different MHC gene products, and if so how the specificity is determined to prevent autoreactivity. Progress in addressing these issues is, however, being made: a recent paper by Karlhofer et al.([4], see also [51) reports the identification of what may be an NK receptor for MIX class I molecules; and studies of human NK cells are beginning to shed light on their recognition mechanism [Gs].~~-49 was originally identified as an antigen on the surface of EL-4 cells recognized by the monoclonal antibody Al [9]. The gene for Ly-49 has been cloned, and the protein shown to be a hom~ odimer of two 45-50 kD subunits [9-111. It is a type II glycoprotein with an extracellular C-terminal domain, and is expressed on a small subpopulation of spleen cells in mice of the B6 strain, Karlhofer et aZ. were drawn to study the possible involvement of Ly-49 in m-cell specificity by the observation that it is encoded