Molecular and functional investigation of the role of HLA-F in immune regulation

HLA-F在免疫调节中作用的分子和功能研究

• 批准号: 10503676
• 负责人: Erin June Adams
• 金额: $ 68.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-06 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503676
• 关键词: 3-Dimensional; Address; Adenoviruses; Adopted; Amino Acids; Antibodies; Antigens; Applications Grants; Area; Autoimmune Diseases of the Nervous System; Autoimmunity; Binding; Biological Assay; Biophysics; Cell surface; Cells; Clone Cells; Data; Decidua; Disease; Effector Cell; Environment; Family; Family member; Funding; Genetic Polymorphism; Goals; HIV; HIV Infections; Health; Homeostasis; Human; Immune; Immunity; Infection; Invaded; Investigation; KLRD1 gene; Length; Ligands; Link; Major Histocompatibility Complex; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Natural Killer Cells; Peptides; Play; Post-Translational Protein Processing; Pregnancy; Production; Protein Isoforms; Proteins; Publishing; RNA Splicing; Reagent; Receptor Cell; Recombinants; Reproduction; Role; Source; Specificity; Structure; T-Lymphocyte; Testing; Variant; Viral; Work; biophysical analysis; cancer cell; cell type; conformer; fetal; immunoregulation; member; pathogen; protein complex; receptor; three dimensional structure; trafficking; tumor

Project Summary/Abstract HLA-F is a nonclassical class I MHC (Ib) molecule that has been found expressed on a variety of cancers, shown to play a role in HIV and adenoviral infection, the neurological autoimmune disease ALS and is expressed throughout pregnancy. Despite the potential importance of this protein in these conditions, little is known about this molecule in terms of its function or even in which conformational state it is expressed. We have recently shown that, in addition to being expressed as a heavy chain only state, or open conformer (HLA-FOC), HLA-F can also be expressed as a bon fide peptide presenting molecule, associated with the β2m subunit (pHLA-F). Peptides are presented in an unconventional way, with the N-terminus not anchored within the groove and the potential for post-translational modifications featuring in peptide anchoring. Despite these advances, there remains much unknown about how these conformer states are regulated, how it engages its various receptors in each of these conformer states, and the role of HLA-F in its various environments of tumor surveillance, autoimmunity and reproduction. Thus, the aims of this proposal focus on addressing these questions and are: Aim 1: To investigate, structurally and functionally, the various conformer states that HLA-F adopts in human health and disease. We will pursue structural studies of the HLA-F isoforms to understand how these two states differ from each other. Using conformer-specific antibodies, we will determine what cell types express which (or both) forms and how this differs between healthy and disease cells. We will also pursue peptide elution studies from a range of human sources to determine if the peptide repertoire shifts depending on cellular origin or disease. Aim 2: To identify and analyze the factors that regulate the production or interchange of HLA- F conformers and splice forms in a cell. We will explore the cellular factors that may play a role in switching HLA-F between peptide-loaded and HLA-FOC as well as an intriguing splice variant of HLA-F of unknown function. Finally, in Aim 3 we seek to establish the receptor repertoire that engage HLA-F in its various conformer states, determine the molecular basis for their association and study the functional consequences of their binding. We will employ the structural, biophysical and functional expertise of the Adams lab to determine the receptor repertoire that engage these conformer states of HLA-F and study them at the functional and molecular level.

项目总结/文摘