Recognition of major histocompatibility complex class I antigens by natural killer cells.
Recognition of major histocompatibility complex class I antigens by natural killer cells.
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DOI：
10.1084/jem.180.2.417
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发表时间：
1994-08-01
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影响因子：
--
通讯作者：
Trinchieri G
中科院分区：
文献类型：
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作者：
Trinchieri G
自然杀伤（NK）细胞是细胞毒性淋巴细胞，其在不存在先前刺激的情况下裂解多种靶细胞，包括肿瘤细胞、病毒或细胞内细菌感染的细胞，以及在某些情况下，正常细胞（1）。因此，NK细胞代表了对感染、肿瘤生长或组织稳态的其他致病性改变的第一道防线。与T或B淋巴细胞不同，NK细胞不表达分子重排的受体，特别是在其表面上既不重排也不表达编码T细胞受体（TCR）的四种基因中的任何一种。NK细胞的活化不仅导致细胞毒性，而且导致细胞因子的快速分泌，特别是干扰素-7（IFN-3）、粒细胞/巨噬细胞集落刺激因子（GM-CSF）和肿瘤坏死因子（TNF）（1）。NK细胞识别和破坏靶细胞的能力被认为是非特异性的，可能是由多种粘附样受体介导的，这些受体识别病理靶细胞上表面分子表达模式的改变。能够激活NK细胞细胞毒性和细胞因子产生的最佳表征的受体是IgG型伊利亚的Fc的受体（Fc 3RIIIA或CD 16）。CD 16与CD 3/TCR的3 '链或FceRI的3'链的二聚体相关，并以与通过TCR/CD 3复合物观察到的机制相似的机制介导信号转导（1）。通过CD 16，NK细胞识别IgG抗体包被的靶细胞并介导抗体依赖性细胞毒性（ADCC）。然而，在不存在抗体的情况下，CD 16似乎不参与细胞毒性的诱导（1）。其他细胞毒性触发受体已被描述在NK细胞上，但它们在靶细胞上的配体及其在细胞毒性中的作用尚未阐明。尽管NK细胞的活性被认为是非特异性的，并且与CD 8+细胞毒性T淋巴细胞（CTL）不同，不需要在靶细胞上表达主要组织相容性复合体（MHC）抗原，但多年来已经积累了表明NK细胞识别特异性的证据。Kiessling等人(2)证明NK细胞是负责辐射F1小鼠中亲代骨髓移植物排斥（造血杂交抗性）的效应细胞，表明NK细胞作用的遗传特异性。负责这种抗性的主要基因座Hh-1被定位到H-2DL区域，并且对H-2D a转基因小鼠的研究强烈表明，I类等位基因D d的产物是控制NK细胞遗传特异性的主要决定因素（3）。在大鼠中，NK细胞在体内迅速消除同种异体淋巴细胞以及骨髓细胞（同种异体淋巴细胞毒性，ALC），并且在体外也产生了无反应性NK细胞（4）。控制这种同种异体反应性的遗传因素位于大鼠MHC的dass I区（RT 1-C），但是，与常规杂交抗性不同，在常规杂交抗性中，对排斥的敏感性总是作为隐性性状遗传（抗性作为显性性状遗传），在一些品系组合中，发现对大鼠同种异体反应性NK细胞的排斥和溶解的敏感性显性分离，尽管很少（4）。在几个实验系统中，靶细胞对NK细胞介导的裂解的易感性与其I类MHC抗原的表达成反比（5）。解释NK细胞识别I类低靶细胞的能力的假设之一是”缺失自我假设”，该假设假设NK细胞的一个功能是识别和消除不表达MHC I类分子的细胞（5）。然而，这一假设需要修改，以适应表明NK细胞可能不仅受到存在的影响的研究结果。
N'atural Killer (NK) cells are cytotoxic lymphocytes that, in the absence of prior stimulation, lyse a variety of target cells, including tumor cells, virus-, or intracdlular bacteria-infected cells, and, in some cases, normal cells (1). Thus, NK cells represent a first line of defense to infections, tumor growth, or other pathogenic alterations of tissue homeostasis. Unlike T or B lymphocytes, NK cells do not express molecularly rearranged receptors and, in particular, neither rearrange nor express on their surface any of the four genes encoding the T cell receptor (TCR). Activation of NK cells results not only in cytotoxicity but also in rapid secretion of cytokines, particularly interferon-7 (IFN-3), granulocyte/macrophage colony-stimulatory factor (GM-CSF), and tumor necrosis factor (TNF)(1). The ability of NK cells to recognize and destroy target cells has been considered nonspecific and possibly mediated by multiple adhesionlike receptors recognizing an altered pattern of expression of surface molecules on pathological target cells. The best characterized receptor able to activate NK cell cytotoxicity and cytokine production is the receptor for Fc of IgG type IliA (Fc3RIIIA or CD16). CD16 is associated with dimers of the~" chain of CD3/TCR or of the 3'chain of FceRI, and mediates signal transduction with similar mechanisms as those observed via the TCR/CD3 complex (1). Through CD16, NK cells recognize IgG antibody-coated target cells and mediate antibody-dependent cytotoxicity (ADCC). However, CD16 does not appear to be involved in the induction of cytotoxicity in the absence of antibodies (1). Other cytotoxicity-triggering receptors have been described on NK cells, but their ligands on target cells and their role in cytotoxicity have not been elucidated. Although the activity of NK cells has been considered nonspecific and, unlike CD8 § cytotoxic T lymphocytes (CTL), does not require the expression of major histocompatibility complex (MHC) antigens on target cells, evidence suggesting specificity in NK cell recognition has been accumulating for many years. Kiessling et al.(2) demonstrated that NK cells were the effector cells responsible for the rejection of parental bone marrow grafts in irradiated F1 mice (hematopoietic hybrid resistance) indicating a genetic specificity in NK cell action. The major locus responsible for this resistance, Hh-1, was mapped to the H-2DL region and studies with H-2D a transgenic mice strongly suggested that the product of the class I allele D d is a major determinant governing the genetic specificity of NK cells (3). In rats, NK cells rapidly eliminate in vivo allogeneic lymphocytes as well as bone marrow cells (allogeneic lymphocyte cytotoxicity, ALC), and aUoreactive NK calls were also generated in vitro (4). The genetic dements controlling this alloreactivity are in a dass I region (RT1-C) of the rat MHC, but, unlike routine hybrid resistance in which the susceptibility to rejection was always inherited as a recessive trait (and resistance as a dominant one), susceptibility to both rejection and lysis by rat alloreactive NK cells was found to segregate dominantly, although rarely, in some strain combinations (4). In several experimental systems, the susceptibility of target cells to NK call-mediated lysis is inversely proportional to their expression of class I MHC antigens (5). One of the hypotheses to explain the ability of NK cells to recognize class I low target cells is the" missing self hypothesis" that postulates that one function of NK cells is to recognize and eliminate cells that do not express MHC class I molecules (5). This hypothesis needs to be modified, however, to accommodate findings suggesting that NK cells may be affected not only by the presence …