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: 10523733
• 负责人: MALINI RAGHAVAN
• 金额: $ 18.83万
• 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/10523733
• 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 group; Genes; Genotype; 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 of activation protein; Molecular; Mutate; Peptides; Persons; Population; Prevalence; Property; Proteins; Proteome; Race; 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; base; beta-2 Microglobulin; cancer cell; knowledge of results; pathogen; peptide I; predictive tools; protein aminoacid sequence; 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.

CD 8 + T细胞在主要组织相容性复合物I类（MHC-I）的背景下识别短肽抗原。 I）蛋白质。人类白细胞抗原（HLA）HLA-A、HLA-B和HLA-C三组基因编码 人MHC-I（HLA-I）蛋白质的重链，其还含有轻链（β2-微球蛋白）和 肽。HLA-A、HLA-B和HLA-C基因具有高度多态性。在细胞中，单个HLA-I同种异型可以 与许多来源于细胞内蛋白质的肽结合。细胞感染诱导特异性 病原体衍生肽，其可以触发CD 8 + T细胞识别和免疫。近期质量 质谱（MS）研究已经鉴定了数千种与HLA-I结合的肽的序列 同种异型，单个肽段。对这些肽序列的检查导致了可变的 HLA-I同种异型之间的肽库大小和导致的CD 8 + T细胞应答宽度的变化 SARS-Cov 2感染和COVID-19疫苗接种。为了解决这一假设，在拟议的研究中， 将使用定量高分辨率质谱（MS）来测量自身肽的差异 所选HLA-B同种异型的库大小。库大小变化的基础因素将是 考察此外，诱导CD 8 + T细胞活化的SARS-CoV-2刺突表位的宽度将是 使用来自已接种COVID-19疫苗的选定HLA基因型献血者的血液进行测量， 检查HLA-I同种异型之间表位宽度变异的流行率。综合来看，这些研究 解决可变HLA-I肽组缺陷的患病率和后果，重点是免疫 由COVID-19疫苗引起。从这些研究中获得的知识将为HLA的关键方面提供信息- 生物学和疫苗免疫。