DEVELOPMENT OF HUMAN NATURAL KILLER CELL KIR

人类外周血中的自然杀伤(NK)细胞群由数百个克隆组成，每个克隆由KIR和CD94：NKG2受体的独特组合定义。这种多样性被认为是为了增加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。某些受体与HLAI类分子的多态决定簇结合，产生抑制信号，使NK细胞具有自我耐受性。其中一个这样的受体KIR3DL1，是具有Bw4表位的三分之一的HLA-B同种异型的特异性受体。KIR3DL1的表达是具有Bw4表位的三分之一的HLA-B同种异型所特有的。KIR3DL1的表达是具有Bw4表位的三分之一的HLA-B同种异型所特有的。NK细胞KIR3DL1的表达在个体内是固定的，但个体之间的表达方式是由基因决定的。我们假设KIR3DL1的表达模式在很大程度上是由KIR基因家族中的遗传多态决定的，而人类白细胞抗原(HLA)多态的影响较小。在目标1中，将通过对兄弟姐妹的分析来检验这一假设，在该分析中，KIR3DL1的模式将与KIR和HLA型相关。虽然小鼠没有KIR，但黑猩猩NK细胞使用这种类型的受体。然而，KIR3DL1的黑猩猩同源物具有A和B同种异型的特异性，这与人类KIR3DL1的Bw4特异性截然不同。这种高度亲缘关系的物种之间的差异与NK细胞受体对病原体变化的适应一致。KIR3DL1的变化特异性将在目标2中通过涉及区分人类和黑猩猩KIR的20个氨基酸替换的突变来检验。该策略将研究突变SIN的MHC 1类特异性，即结构域、半结构域和单一氨基酸被其他物种中存在的那些替换。这项研究将确定改变突变体的特异性的遗传因素，这些突变体中的结构域、半结构域和单一氨基酸被其他物种中的那些取代。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KIR3DL1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.