Influences of HLA Class I Polymorphisms on Immune Responses

摘要 人类白细胞抗原（human leukocyte antigen，HLA）I类分子对感染性疾病和肿瘤的发生有着深远的影响 结果，通过对CD 8 + T细胞和自然杀伤（NK）细胞介导的免疫的影响。三组基因， HLA-A、HLA-B和HLA-C编码HLA I类蛋白。这些基因是最具多态性的 人类基因，在人类中发现了数千个等位基因。每种同种异型都有一组独特的肽， 细胞表面和与HLA I类分子复合的单个肽赋予了对 通过T细胞受体（TCR）识别CD 8 + T细胞。在规范的教科书定义的HLA I类程序集中， 在该途径中，与HLA I类分子结合的肽通常来源于细胞的细胞质，并且 通过与抗原加工相关的转运蛋白（TAP）转运到内质网（ER）中。 在ER中，肽与HLA I类分子在特定组装引导的过程中组装 如tapasin和一般ER伴侣因子。肽加载形式的HLA I类分子离开 ER，而ER质量控制被认为是回收肽缺陷的HLA I类用于降解，这是由于它们的 相对不稳定。我们最近的一些发现表明，典型的组装途径并不完全 解释了所有细胞中HLA-B同种异型的细胞表面表达模式，此外，肽- 在某些条件下，缺陷型（空）HLA-B确实存在于细胞表面，并且在免疫应答中起作用。 反应基于这些发现，我们的中心假设是HLA-B同种异型在功能上是可分离的 基于它们的空形式的稳定性和它们的肽结合偏好， 这些特性决定了它们对非规范组装途径和相关功能的能力。到 为了验证这一假设，我们研究了HLA-B同种异型在其组成性细胞表面 表达水平和在抗原呈递细胞（APC）中的交叉呈递效率，基于 非规范装配的能力。我们还研究了HLA-B同种异型在其 诱导针对Epstein巴尔病毒（EBV）感染的有效CD 8 + T细胞免疫的能力， 在缺乏TAP的环境中进行组装的能力。最后，给出了微分归纳法和 检测了空HLA-B在CD 8 + T细胞中的新功能和NK细胞功能。这些研究一起 解决了HLA-B基因座的极端多态性，这是进化选择的中心思想， 在HLA I类结构的限定区域内的突变，产生蛋白质折叠的层次结构， 组装表型，这些表型被免疫应答的不同分支利用，以维持多- 分区和多模式监测。这些研究有望指导我们在精密度方面的进展 通过识别特定疫苗靶点的最佳候选HLA-B，为药物提供新的靶点， 对抗HLA-B驱动的自身免疫和药物过敏。

Abstract Human leukocyte antigen (HLA) class I molecules have profound influences on infectious disease and cancer outcomes, via effects on immunity mediated by CD8+ T cells and natural killer (NK) cells. Three sets of genes, HLA-A, HLA-B and HLA-C encode HLA class I proteins. These genes are among the most polymorphic of human genes, with thousands of alleles found in humans. Each allotype presents a unique set of peptides at the cell surface, and individual peptides in complex with HLA class I molecules confer exquisite specificity for recognition by T cell receptors (TCR) of CD8+ T cells. In the canonical textbook-defined HLA class I assembly pathway, peptides that bind to HLA class I molecules are typically derived from the cytoplasm of cells, and transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides assemble with HLA class I molecules in a process that is guided by specific assembly factors such as tapasin and generic ER chaperones. Peptide-loaded versions of HLA class I molecules exit the ER, whereas ER quality control is thought to retrieve peptide-deficient HLA class I for degradation, due to their relative instability. A number of our recent findings indicate that the canonical assembly pathway does not fully account for cell surface expression patterns of HLA-B allotypes in all cells, and additionally that peptide- deficient (empty) HLA-B do exist at the cell surface under some conditions, and are functional in the immune response. Based on these findings, it is our central hypothesis that HLA-B allotypes are functionally separable based on the stabilities of their empty forms and their peptide-binding preferences, and that these characteristics determine their competence for non-canonical assembly pathways and related functions. To test this hypothesis, we examine the model that HLA-B allotypes vary both in their constitutive cell surface expression levels and in cross-presentation efficiencies in antigen presenting cells (APC), based on competence for non-canonical assembly. We also examine the model that HLA-B allotypes vary in their abilities to induce effective CD8+ T cell immunity against Epstein Barr Virus (EBV) infections due to varying competencies for assembly in a TAP-deficient environment. Finally, the models of differential induction and novel functions for empty HLA-B in CD8+ T cell and NK cell functions are examined. Together, these studies address the central idea that the extreme polymorphisms of the HLA-B locus, which are evolutionarily-selected mutations within a confined region of the HLA class I structure, generate a hierarchy of protein folding and assembly phenotypes that are exploited by distinct arms of the immune response to maintain multi- compartmental and multimodal surveillance. These studies are expected to guide our progress in precision medicine by identifying best candidate HLA-B for specific vaccine targets, and provide new targets for combatting HLA-B-driven autoimmunity and drug hypersensitivity.