MHC CLASS I AND KIR GENE EVOLUTION IN HIGHER PRIMATES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。不同和快速进化的病原体的选择已经促使MHC I类和KIR成为控制先天免疫和获得性免疫中杀手淋巴细胞的多样化和快速进化的基因家族。由于人类和小鼠的MHC I类基因非常不同，而KIR基因是灵长类动物特有的，因此我们将在大猩猩身上研究这些基因家族，并将其与人类的同类基因进行比较。这种方法将实现对这些基因家族多样化和共同进化背后的遗传原理的理解，并认识到它们对免疫反应和人类健康的影响。四个具体目标包括以免疫遗传专业知识为基础并以过去五年中获得的大量新信息为基础的综合和独特的攻击。AIMS 1和2将研究新发现的MHC I类基因，这为研究MHC I类基因的出生、分化和死亡提供了一个理想的系统。目的1将验证这样的假设，即该AL基因沿着非常不同的进化轨迹进化，成为猩猩中高度多态的经典I类基因，黑猩猩中非多态的非经典I类基因，以及人类中已灭绝的遗迹基因。在黑猩猩中，AL蛋白具有暗示适应性免疫和先天免疫功能的特性。AIM 2的研究将检测AL的功能特性，并寻找与该配体结合的细胞表面受体。它将揭示人类免疫系统已经失去的功能，无论是通过漂移还是选择。目标3专注于B7301，这是一种异常分化的人类HLA-B等位基因，保留了祖先(类人猿)的特征，并抵制重组。将通过对B7301两侧区域的基因组分析来测试和区分三种可以解释这些不寻常特性的替代模型：选择、染色体重排和种群隔离。猩猩是与人类最接近的物种，其表达的MHC I类基因的含量明显不同。目的4研究猩猩MHC-I和KIR在NK细胞调节中的相互作用。这将检验这样一种假设，即猩猩是一种处于发育中期阶段的物种，在人类中占主导地位的自然杀伤细胞的调节是由人类白细胞抗原-C介导的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selection by diverse and rapidly evolving pathogens has driven MHC class I and KIR to become diverse and fast evolving gene families that control killer lymphocytes in innate and adaptive immunity. Because human and mouse MHC class I genes are so different and KIR genes are primate-specific, these gene families will be studied in the great apes and compared to their human counterparts. This approach will achieve understanding of genetic principles underlying diversification and co-evolution of these gene families, and appreciation of their consequences for immune response and human health. Four specific aims comprise an integrated and unique attack founded on immunogenetic expertise and built upon substantial new information acquired during the last five years. Aims 1 and 2 will study a newly discovered MHC class I gene that provides an ideal system for studying the birth, differentiation and death of MHC class I genes. Aim 1 will test the hypothesis that this AL gene has evolved along very different evolutionary trajectories to become a highly polymorphic 'classical' class I gene in orangutan, a non- polymorphic 'non-classical' class I gene in chimpanzee, and a defunct relic gene in human. In chimpanzee the AL protein has properties suggestive of functions in both adaptive and innate immunity. The investigation of Aim 2 will examine functional properties of AL and search for cell-surface receptors that bind this ligand. It will reveal functions that the human immune system has lost, either through drift or selection. Aim 3 focuses on B 7301, an exceptionally divergent human HLA-B allele that retains ancestral (ape-like) features and has resisted recombination. Three alternative models that can explain these unusual properties: selection, chromosomal rearrangement, and population isolation, will be tested and distinguished by genomic analysis of the regions flanking B 7301. The orangutan is the species closest to humans in which the content of expressed MHC class I genes is markedly different. Aim 4 focuses on orangutan MHC class I and KIR and their interaction in NK cell regulation. This will test the hypothesis that orangutan is a species in which the HLA-C-mediated regulation of NK cells, which is dominant in humans, is at an intermediate stage of development.