Influences of HLA Class I Polymorphisms on Immune Responses

摘要 人类白细胞抗原(人类白细胞抗原)I类分子对传染病和癌症有深远的影响 结果，通过CD8+T细胞和自然杀伤(NK)细胞介导的免疫作用。三组基因， 人类白细胞抗原A、B和C编码人类白细胞抗原I类蛋白。这些基因是最具多态的 人类基因，在人类身上发现了数千个等位基因。每个同种异型在以下位置呈现一组独特的多肽 细胞表面和与人类白细胞抗原I类分子形成的复合体中的个别多肽赋予了人类白细胞抗原I类分子 T细胞受体(TCR)识别CD8+T细胞。在规范教科书定义的HLAI类集合中 途径，与人类白细胞抗原I类分子结合的多肽通常来自细胞质，并且 通过与抗原处理相关的转运蛋白(TAP)运输到内质网(ER)。 在内质网中，多肽与人类白细胞抗原I类分子在特定组装的指导下进行组装 Tapasin和非专利内质网伴侣等因素。人类白细胞抗原I类分子的多肽版本退出了 呃，而ER质控被认为可以回收缺乏多肽的HLAI类进行降解，因为它们 相对不稳定。我们最近的一些发现表明，正则组装途径并不完全 解释了所有细胞中人类白细胞抗原-B同种异型的细胞表面表达模式，此外，多肽- 在某些条件下，缺陷(空)的人类白细胞抗原B确实存在于细胞表面，并在免疫中起作用 回应。基于这些发现，我们的中心假设是，人类白细胞抗原-B同种异型在功能上是可分离的 基于它们空形式的稳定性和它们的多肽结合偏好，并且这些 特性决定了它们对非规范组装途径和相关功能的能力。至 为了验证这一假设，我们检验了人类白细胞抗原-B同种异型在构成细胞表面的变化模型 抗原提呈细胞(APC)的表达水平和交叉提呈效率，基于 非规范装配的能力。我们还研究了人类白细胞抗原-B同种异型在其 对EB病毒感染诱导有效的CD8+T细胞免疫的能力 在TAP不足的环境中装配的能力。最后，给出了微分归纳法和微分归纳法 对CD8+T细胞和NK细胞中空人类白细胞抗原B的新功能进行了研究。总而言之，这些研究 提出的中心思想是，人类白细胞抗原-B基因座的极端多态是进化选择的 在HLAI类结构的受限区域内的突变，产生蛋白质折叠的层次结构和 由免疫反应的不同手臂利用的组装表型，以维持多个- 分区和多式监视。这些研究有望指导我们在精确度方面的进展 通过确定特定疫苗靶点的最佳候选HLA-B来治疗药物，并提供新的靶点 对抗人类白细胞抗原B诱导的自身免疫和药物超敏反应。

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.