Role of mCD1D2 in iNKT cell development and functions

mCD1D2 在 iNKT 细胞发育和功能中的作用

• 批准号: 9431944
• 负责人: Laurent Gapin
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-07 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9431944
• 关键词: Adopted; Affect; Agonist; Amino Acids; Animals; Antigen Presentation; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; C57BL/6 Mouse; CRISPR/Cas technology; Cells; Cellular biology; Chromosomes, Human, Pair 3; Crystallization; Cysteine; Cytotoxic T-Lymphocytes; Data; Development; Disease; Engineering; Epithelial Cells; Exons; Fatty Acids; Frameshift Mutation; Gene Duplication; Genes; Genetic; Genetic Transcription; Genomics; Glycolipids; Health; High-Throughput Nucleotide Sequencing; Histocompatibility Antigens Class I; Homeostasis; Human; Immune; Immune response; Immunity; Immunologics; Inbred BALB C Mice; Length; Lipids; Lymphocyte; Malignant Neoplasms; Mediating; Messenger RNA; Modification; Molecular Conformation; Mouse Strains; Mus; Mutation; Nature; Neomycin resistance gene; Outcome; Pathway interactions; Population; Positioning Attribute; Predisposition; Protein Isoforms; Proteins; Publishing; Reagent; Reporting; Role; Sequence Homology; Serological; Shapes; Signal Transduction; Structure; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Therapeutic Uses; Thymus Gland; Tissues; Transcript; Tryptophan; Variant; ZNF145 gene; antigen binding; cytokine; disulfide bond; duplicate genes; gene product; improved; in vivo; mouse model; programs; protein expression; response; thymocyte; transcription factor

Project Summary Invariant Natural Killer T (iNKT) cells are a type of immune cell that is numerally small but immunologically important to our health. Numerous studies in humans and mice have suggested that if you do not have a normal population of iNKT cells, you have an increased susceptibility to autoimmune diseases and cancers. In the mouse, two genes with 95% sequence homology are encoding for the CD1d molecules. Recognition of lipid antigens presented by CD1d molecules is absolutely required for the development and functions of iNKT cells. Early findings argued that the second CD1d-encoding gene, CD1D2, does not play any role in iNKT cells biology. However, in complete departure from the current dogma, our preliminary data show that the CD1D2 gene is expressed in certain mouse strains. Furthermore, the crystal structure of the CD1d2 protein and our preliminary functional data, show that the antigen-binding groove of CD1d2 is restricted in size compared to CD1d1 and does not accommodate presentation of antigens with long acyl-chains. Although the lipid portions of antigens are buried in the CD1d groove, several reports have shown that the composition of the fatty acids, including the length, the degree of insaturation and the presence of other modifications, strongly influence antigenic potency. The proposed studies aim at examining how CD1d1 molecules engineered to mimic antigen presentation of CD1d2 molecules affect the development of iNKT cells in vivo. These studies will open up substantial new possibilities for understanding iNKT cell development and effector programming so that it can be exploited for therapeutic usage to improve human health.

项目摘要 不变自然杀伤T细胞(INKT)是一种免疫细胞，其数量很小，但 免疫学上对我们的健康很重要。在人类和老鼠身上的大量研究表明，如果你这样做了 没有正常的iNKT细胞群，你对自身免疫性疾病的易感性增加， 癌症。 在小鼠中，两个序列同源性为95%的基因正在编码CD1d分子。 CD1d分子提呈的脂类抗原的识别是形成和发展必不可少的 INKT细胞的功能。早期的发现认为，第二个编码CD1d的基因CD1D2不起任何作用 在iNKT细胞生物学中的作用。然而，我们的初步数据显示，与当前的教条完全背道而驰 CD1D2基因在某些小鼠品系中表达。此外，还研究了CD1d2的晶体结构 蛋白质和我们的初步功能数据表明，CD1d2的抗原结合沟在大小上受到限制。 与CD1d1相比，并且不适合呈递具有长酰链的抗原。尽管 抗原的脂类部分被埋在CD1d沟中，一些报告表明， 脂肪酸，包括长度、不饱和度和其他修饰的存在，强烈 影响抗原性。 这项拟议的研究旨在研究CD1d1分子是如何通过基因工程来模拟抗原的。 CD1d2分子的提呈影响体内iNKT细胞的发育。这些研究将开启 理解iNKT细胞发育和效应器编程的实质性新可能性，以便它能够 被开发用于治疗用途，以改善人类健康。