Modulation of CD8+ T Cell Responses by HLA-F

CD8+T细胞是清除病毒感染细胞和肿瘤细胞的关键。它们能识别呈现的抗原 由人类白细胞抗原I类(人类白细胞抗原I类)分子。人类白细胞抗原F是一种非经典的人类白细胞抗原I类分子 最近，由于它在几种病毒感染和癌症中的潜在意义而引起了很多关注。 尽管之前认为人类白细胞抗原-F只以开放构象(无肽)的形式表达，但最近 研究表明，人类白细胞抗原-F也可以以多肽相关形式表达。由于它的局限性 在病毒感染控制和肿瘤免疫治疗中，人类白细胞抗原-F是一个有吸引力的靶点。然而，它 目前尚不清楚HLA-F是否以及如何调节CD8+T细胞的功能。 在这项建议中，我们希望通过以下几个方面来阐述人类白细胞抗原-F在CD8+T细胞反应中的作用 具体目的：目的1：确定人类白细胞抗原F的递呈途径。这两个方面的积累 内质网和细胞表面的开放构象提示人类白细胞抗原F的多肽负载量。 急诊室效率低下。我们的初步研究表明，这是一种非常规的抗原提呈途径。我们会 确定多肽在哪里以及如何加载到人类白细胞抗原F，这将有助于未来的疫苗设计。目标2： 检测人类白细胞抗原F对CD8+T细胞活化的影响。人类白细胞抗原F特异性CD8+T细胞将从 有病原体经验的捐献者的外周血液。分离的CTL将用于研究人类白细胞抗原-F 向CTL呈递多肽。由于人类白细胞抗原-F主要以开放构象形式表达，我们还将 检测人类白细胞抗原F开放构象对CD8+T细胞活化的影响。 这一方案的成功完成将揭示人类白细胞抗原F的抗原提呈机制以及如何 人类白细胞抗原-F调节CD8+T细胞反应，有助于开发基于人类白细胞抗原-F的免疫疗法。

CD8+ T cells are critical for clearance of viral-infected cells and tumor cells. They recognize antigens presented by human leukocyte antigen class I (HLA-I) molecules. HLA-F is a non-classical HLA-I molecule that has recently been drawing a lot of attention due to its potential significance in several viral infections and cancers. Although HLA-F was previously believed to be expressed only as open conformers (without peptide), recent studies showed that HLA-F can also be expressed as peptide-associated form. Due to its limited polymorphisms, HLA-F is an attractive target for viral infection control and cancer immunotherapy. However, it is still not clear whether and how HLA-F modulates the function of CD8+ T cells. In this proposal, we expect to address the function of HLA-F in CD8+ T cell responses with the following specific aims: Aim 1: Determine the HLA-F antigen presentation pathway. Both of the accumulation in the endoplasmic reticulum (ER) and the open conformation on the cell surface indicate peptide loading of HLA-F in the ER is inefficient. Our preliminary study suggests an unconventional antigen presentation pathway. We will determine where and how peptides are loaded to HLA-F, which will facilitate the future vaccine design. Aim 2: Determine the effect of HLA-F on CD8+ T cell activation. HLA-F specific CD8+ T cells will be isolated from peripheral blood of pathogen-experienced donors. The isolated CTLs will be used to investigate how HLA-F presents peptides to CTL. Since HLA-F is predominantly expressed as open conformers, we will also determine the effect of HLA-F open conformers on CD8+ T cell activation. Successful completion of this proposal will reveal the antigen presentation mechanisms of HLA-F and how HLA-F modulates CD8+ T cell responses, contributing to developing HLA-F based immunotherapies.