Origins of Diversity at Human Classical MHC Class I Genes

描述(申请人提供)：人类NK细胞在免疫和生殖中的功能由杀伤细胞免疫球蛋白样受体(KIR)和主要组织相容性复合体(MHC)I配体之间的高度多态相互作用控制。总体而言，这些相互作用使人类免疫系统个体化，并个别地与疾病易感性和临床移植的结果相关。MHC I类和KIR进化的速度如此之快，以至于只有高等非人类灵长类动物(类人猿和猴子)才有与人类成分相同的东西，因此这些物种提供了最有效的动物模型。黑猩猩已被证明提供了信息，因为它们的MHC与人类白细胞抗原区域非常相似，观察到的差异可能有助于它们对某些人类感染的相对抵抗力。虽然总的来说，黑猩猩在遗传上比人类更多样化，但Patr-A的多态程度低于人类白细胞抗原-A，并且缺乏与人类最常见的同种异型--人类白细胞抗原-A*02等同的基因。在此背景下，我们研究了Patr-AL，一种新的黑猩猩特有的MHC I类基因，它由一个新的非多态基因编码，具有独特的组织分布和类似于人类白细胞抗原-A*02的多肽结合特异性。在目标1中，将进行PATR-AL的结晶学研究，以确定这种共同的特异性是收敛还是发散进化的结果。人类AL候选基因已被发现，并与非高加索人群的人类白细胞抗原单倍型相关。将确定该基因在MHC中的位置，并评估其编码蛋白的功能。虽然许多黑猩猩Patr-B同种异型携带KIR2DL2/3识别的C1表位，但在人类中，这种B同种异型的谱系表现为单一的、特征不佳的同种异型，即HLA-B*7301，它广泛分布，但对标志着HLA-B的重组具有抵抗力。我们在目标2中建议研究B*7301作为KIR配体的功能作用。通过对人群中的B*73和类人猿中的B*73的分析，我们将重建人类的历史。事实证明，猩猩提供了丰富的信息，因为在人类系统中占主导地位的MHC-C和KIR之间的相互作用更简单，类似于构建的中间阶段。在目标3中，我们将检验一种假设，即MHC-A和MHC-B之间的相互作用和KIR在调节猩猩NK细胞方面比在人类中更占优势。正如这项研究计划的先前成果反复证明的那样，这些研究将为人类免疫系统的工作机制提供有价值的新见解和观点，而这些见解和观点永远不可能从单独研究人类或小鼠模型中获得。

DESCRIPTION (provided by applicant): Human NK cell functions in immunity and reproduction are controlled by highly polymorphic interactions between killer cell immunoglobulin-like receptors (KIR) and major histocompatibility complex (MHC) I ligands. In aggregate these interactions individualize human immune systems and individually they correlate with disease susceptibilities and outcome of clinical transplantation. The rapidity with which MHC class I and KIR evolve is such that only the higher non-human primates (apes and monkeys) have equivalents to the human components and thus these species provide the most valid animal models. Chimpanzees have proved informative, because their MHC is very similar to the HLA region, the observed differences being likely to contribute to their relative resistance to certain human infections. Although chimpanzees are overall more genetically diverse than humans, Patr-A is less polymorphic than HLA-A, and lacks an equivalent of HLA-A*02, the most common human allotype. In this context we studied Patr-AL, a novel and chimpanzee-specific MHC class I that is encoded by a novel, non- polymorphic gene, with distinctive tissue distribution, and a peptide- binding specificity like HLA-A*02. In Aim 1 crystallography of Patr-AL will be undertaken to determine if this common specificity is the result of convergent or divergent evolution. A candidate human AL gene has been identified and associated with HLA haplotypes from non-caucasoid populations. The location of this gene in the MHC will be determined, and the function of its encoded protein assessed. Whereas many chimpanzee Patr-B allotypes carry the C1 epitope recognized by KIR2DL2/3, this lineage of B allotypes is represented in humans by a single poorly characterized allotype, HLA-B*7301, that is widely dispersed, but resistant to the recombination that marks HLA-B. We propose in Aim 2 to study the functional role of B*7301 as a ligand for KIR. Through analysis of B*73 in populations and the B*73 counterparts in apes, we will reconstruct the human history of HLA-B*7301. Orangutans have proved informative because the interactions between MHC-C and KIR that dominate the humans system, is simpler and resembles an intermediate stage of construction. In Aim 3 we will test the hypothesis that interactions between MHC-A and MHC-B and KIR are more dominant in the regulation of orangutan NK cells than in humans. As has repeatedly been demonstrated by the prior achievements of this research program, these studies will provide valuable new insights and perspective to the workings of the human immune system that could never be obtained from studying either humans alone or mouse models.