DEVELOPMENT OF HUMAN NATURAL KILLER CELL KIR

人外周血中的自然杀伤（NK）细胞群体由数百个克隆组成，每个克隆由KIR和CD 94：NKG 2受体的独特组合定义。这种多样性被认为增加了NK细胞对感染、恶性肿瘤和移植骨髓的反应的广度和敏感性。某些受体参与HLA I类分子的多态性决定簇，产生抑制信号，使NK细胞能够自我耐受。一种这样的受体KIR 3DL 1对具有Bw 4表位的HLA-B同种异型的三分之一具有特异性。KIR 3DL 1的表达对具有Bw 4表位的三分之一的HLA-B同种异型具有特异性。KIR 3DL 1的表达对具有Bw 4表位的三分之一的HLA-B同种异型具有特异性。NK细胞对KIR 3DL 1的表达在个体内是固定的，但在个体之间以遗传决定的方式变化。我们假设KIR 3DL 1的表达模式主要由KIR基因家族的遗传多态性决定，而HLA多态性的输入较少。在目的1中，该假设将通过同胞分析来检验，其中KIR 3DL 1的模式将与KIR和HLA类型相关。虽然小鼠没有KIR，但这种类型的受体被黑猩猩NK细胞所使用。然而，KIR 3DL 1的黑猩猩同源物对A和B同种异型具有特异性，这与人KIR 3DL 1的Bw 4特异性非常不同。高度相关物种之间的这种差异与NK细胞受体对病原体变化的适应性一致。在目的2中，通过涉及区别人和黑猩猩KIR的20个氨基酸取代的诱变来检查KIR 3DL 1的变化的特异性。研究策略是研究突变体的MHC 1类特异性，即哪些结构域、半结构域和单个氨基酸被其他物种中存在的结构域、半结构域和单个氨基酸取代。这项研究将确定改变突变体特异性的遗传因素，其中结构域，半结构域和单个氨基酸被其他物种中存在的氨基酸取代。这项研究将确定改变单个NK细胞受体的特异性和表达的遗传因素。通过关注KIR 3DL 1受体，我们希望建立适用于其他NK细胞受体的原理。

Populations of natural killer (NK) cells in human peripheral blood consists of hundreds of clones, each defined by a unique combination of KIR and CD94:NKG2 receptors. This diversity is proposed to increased the breadth and sensitivity of the NK cell response to infection, malignancy and transplanted bone marrow. Certain of the receptors engage polymorphic determinants of HLA class I molecules, developing inhibitory signals which enable NK cells to be self-tolerant. One such receptor, KIR3DL1, is specific for the one third of HLA-B allotype having the Bw4 epitopes. The expression of KIR3DLl, is specific for the one third of HLA-B allotypes having the Bw4 epitope. The expression of KIR3DLl, is specific for the one third of HLA-B allotypes having the Bw4 epitope. The expression of KIR3DLl by NK cells is fixed within an individual, but varies between individuals in a way that is genetically determined.. We hypothesize that patterns of KIR3DL1 expression are largely determined by genetic polymorphisms in the KIR gene family, with a lesser input from HLA polymorphisms. In Aim 1 this hypothesis will be tested by an analysis of sibling in which patterns of KIR3DLl will be correlated with KIR and HLA type. Whereas mice do not have KIR, this type of receptor is used by chimpanzee NK cells. However, the chimpanzee homologue of KIR3DL1 has a specificity for A and B allotypes that is quite distinct from the Bw4 specificity of human KIR3DLl. This difference between highly related species is consistent with adaptation of NK cell receptors to changes in pathogens. The changing specificity of KIR3DLl will be examined in Aim 2 by mutagenesis involving the twenty amino-acid substitutions that distinguish the human and chimpanzee KIR. The strategy will be to study the MHC class 1 specificity of mutant sin which domains, half-domains and single amino acids are replaced by those present in the other species. This investigation will determine the genetic factors that change the specificity of mutants in which domains, half-domains and single amino acids are replaced by those present in the other species. This investigation will determine the genetic factors that change the specificity and expression of a single NK-cell receptor. By focusing on the KIR3DLl receptor we hope to establish principles that will apply to other NK-cell receptors.