Origins of Diversity at Human Classical MHC Class I Genes

描述（由申请方提供）：人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性相互作用控制。总的来说，这些相互作用使人类免疫系统个体化，并且单独地，它们与疾病易感性和临床移植的结果相关。MHC I类和KIR进化的速度是如此之快，以至于只有高等非人灵长类动物（猿和猴）具有与人类组分相当的组分，因此这些物种提供了最有效的动物模型。黑猩猩已经证明了信息，因为它们的MHC与HLA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。虽然黑猩猩的遗传多样性总体上高于人类，但Patr-A的多态性低于HLA-A，并且缺乏HLA-A*02的等价物，HLA-A*02是最常见的人类同种异型。在这种情况下，我们研究了Patr-AL，一种新的黑猩猩特异性MHC I类，由一种新的非多态性基因编码，具有独特的组织分布和肽结合特异性，如HLA-A*02。在目标1中，将进行Patr-AL的晶体学研究，以确定这种共同的特异性是趋同进化还是趋异进化的结果。一个候选人AL基因已被确定，并与非高加索人群的HLA单倍型。将确定该基因在MHC中的位置，并评估其编码蛋白的功能。尽管许多黑猩猩Patr-B同种异型携带由KIR 2DL 2/3识别的C1表位，但这种B同种异型的谱系在人类中由单一的表征不佳的同种异型HLA-B *7301代表，其广泛分散，但对标记HLA-B的重组具有抗性。我们在目的2中提出研究B*7301作为KIR配体的功能作用。通过对B*73在人群中的分布和B*73在猿类中的分布的分析，我们将重建HLA-B*7301的人类历史。猩猩已经证明了信息，因为MHC-C和KIR之间的相互作用主导人类系统，更简单，类似于一个中间阶段的建设。在目标3中，我们将检验以下假设：MHC-A和MHC-B与KIR之间的相互作用在猩猩NK细胞的调节中比在人类中更占主导地位。正如该研究项目先前的成就一再证明的那样，这些研究将为人类免疫系统的工作提供有价值的新见解和视角，而这些见解和视角永远无法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.