Modulation of CD8+ T Cell Responses by HLA-F

HLA-F 对 CD8 T 细胞反应的调节

• 批准号: 10190617
• 负责人: Jie Geng
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-09 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190617
• 关键词: Address; Affinity; Alleles; Amino Acids; Antigen Presentation; Antigen Presentation Pathway; Antigens; Attention; Binding; Binding Sites; Blood group antigen f; CD8-Positive T-Lymphocytes; CD8B1 gene; CD94 Antigen; Cell surface; Cells; Complex; Development; Endoplasmic Reticulum; Ensure; Epitopes; Future; Genetic Polymorphism; Goals; HLA Antigens; HLA-A gene; HLA-B Antigens; Histocompatibility Antigens Class I; Human Herpesvirus 4; Immune; Immune response; Immunotherapy; Individual; Infection Control; Ligands; MHC Class I Genes; Molecular Chaperones; Molecular Conformation; Natural Killer Cells; Pathway interactions; Peptides; Population; Proteins; Provider; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Vaccine Design; Variant; Viral; Viral Cancer; Virus Diseases; antigen processing; antigen-specific T cells; antigenic peptide transporter; base; cancer immunotherapy; conformer; emerging pathogen; experience; fight against; invariant chain; neoplastic cell; pathogen; peripheral blood; recruit; trafficking; tumor; universal vaccine

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.

CD8+ T细胞是清除病毒感染细胞和肿瘤细胞的关键。它们能识别抗原