HLA class I peptidome diversities and CD8+ T cell responses to COVID-19 vaccines

HLA I 类肽组多样性和 CD8 T 细胞对 COVID-19 疫苗的反应

• 批准号: 10632096
• 负责人: MALINI RAGHAVAN
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632096
• 关键词: 2019-nCoV; Address; Alleles; Antigens; Binding; Binding Sites; Biology; Blood; Blood donor; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 vaccination; COVID-19 vaccine; Cell surface; Cells; Cellular Assay; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Dependence; Disease; Disease Outcome; Epitopes; Ethnic Population; Genes; Genotype; Globulins; HIV; HLA Antigens; Histocompatibility Antigens Class I; Human; Immune; Immune response; Immunity; Individual; Infection; Infectious Agent; Knowledge; Lead; Light; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Measurable; Measures; Mediator; Molecular; Mutate; Peptides; Persons; Population; Prevalence; Property; Proteins; Proteome; Resolution; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Specificity; Stains; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Translating; Vaccinated; Vaccines; Variant; Viral; Viral Cancer; Virus; Virus Diseases; beta-2 Microglobulin; cancer cell; knowledge of results; pathogen; peptide I; predictive tools; protein aminoacid sequence; racial population; tapasin; vaccine efficacy

CD8+ T cells recognize short peptide antigens in the context of major histocompatibility complex class I (MHC- I) proteins. Three sets of genes, the human leukocyte antigens (HLA) HLA-A, HLA-B and HLA-C encode the heavy chains of human MHC-I (HLA-I) proteins, which also contain a light chain (β2-microglobulin) and a peptide. The HLA-A, HLA-B and HLA-C genes are highly polymorphic. In cells, individual HLA-I allotypes can bind to many peptides derived from intracellular proteins. Cell infection induces the binding of specific pathogen-derived peptides, which can trigger CD8+ T cell recognition and immunity. Recent mass spectrometric (MS) studies have identified the sequences of thousands of peptides that bind to HLA-I allotypes, the individual peptidomes. Inspections of these peptide sequences lead to the hypothesis of variable peptide repertoire sizes among HLA-I allotypes and resulting variations in the breadth of CD8+ T cell responses to SARS-Cov2 infection and COVID-19 vaccination. To address this hypothesis, in the proposed studies, quantitative high resolution mass spectrometry (MS) will be used to measure differences in self-peptide repertoire sizes for selected HLA-B allotypes. Factors that underlie variations in repertoire sizes will be examined. Additionally, the breadth of SARS-CoV-2 Spike epitopes that induce CD8+ T cell activation will be measured using blood from select HLA genotyped blood donors who have been vaccinated against COVID-19, examining the prevalence of epitope breadth variations among HLA-I allotypes. Taken together, these studies address the prevalence and consequences of variable HLA-I peptidome diversities, with a focus on immunity induced by COVID-19 vaccines. The knowledge resulting from these studies will inform on key aspects of HLA- I biology and vaccine-indued immunity.

CD8+T细胞在主要组织相容性复合体I类(MHC-1)背景下识别短肽抗原 I)蛋白质。人类白细胞抗原(HLAA)、HLAB和HLAC三组基因编码 人类MHC-I(β-I)蛋白的重链，也包含轻链(HLA2-微球蛋白)和 多肽。HLAA、HLAB和HLAC基因具有高度的多态性。在细胞中，个别的人类白细胞抗原-I同种异型可以 可与许多来源于细胞内蛋白的多肽结合。细胞感染诱导特异性结合 病原体衍生的多肽，可触发CD8+T细胞识别和免疫。近期质量 光谱(MS)研究已经确定了数千个与人类白细胞抗原-I结合的多肽的序列 同种异型，个别的多肽。对这些肽序列的检查导致了变量假说 人类白细胞抗原-I同种异型之间的多肽谱系大小及其导致的CD8+T细胞反应广度的差异 到感染SARS-Cov2和接种新冠肺炎疫苗。为了解决这一假设，在拟议的研究中， 定量高分辨质谱学(MS)将被用来测量自身多肽的差异 选定的人类白细胞抗原-B同种异型的谱系大小。曲目大小变化背后的因素将是 检查过了。此外，诱导CD8+T细胞激活的SARS-CoV-2尖峰表位的广度将是 使用已接种COVID-19疫苗的精选HLA型献血者的血液进行测量， 检测在人类白细胞抗原-I同种异型之间表位宽度变化的流行率。总而言之，这些研究 解决不同的人类白细胞抗原-I型多肽多样性的流行和后果，重点是免疫 由新冠肺炎疫苗诱导。这些研究所产生的知识将为人类白细胞抗原的关键方面提供信息。 I生物学和疫苗诱导的免疫力。