Development of CD1d-restricted NKT cells

CD1d 限制性 NKT 细胞的发育

• 批准号: 7623863
• 负责人: ALBERT S. BENDELAC
• 金额: $ 37.14万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623863
• 关键词: Adaptor Signaling Protein; Affinity; Agonist; Alphaproteobacteria; Autoimmune Process; Automobile Driving; B-Lymphocytes; Biochemistry; Biological Assay; Biological Models; Cell Lineage; Cell Surface Receptors; Cells; Communicable Diseases; Complex; Detection; Development; Disease; Emerging Communicable Diseases; Enzymes; Exhibits; Family member; Frequencies; Funding; Glycosphingolipids; Goals; Human; Hybrids; IL2RA gene; Immunity; Individual; Inflammatory; Knock-out; Knowledge; Ligands; Lymphocyte; Mainstreaming; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Outcome; Pathway interactions; Pattern; Phenotype; Population; Predisposition; Principal Investigator; Property; Reverse Transcriptase Polymerase Chain Reaction; Rickettsiales; Role; SLAM family receptor; Signal Transduction; Specificity; Staging; T-Cell Development; T-Lymphocyte; Testing; Thymocyte Development; Thymus Gland; Tissues; Transgenic Organisms; Transplantation; UDP-galactose beta-D-galactosyl-1,4-glycosylceramide alpha-1,3-galactosyltransferase; Variant; Work; cell type; chemokine; cytokine; disease phenotype; immunoregulation; in vivo; knowledge base; macrophage; microbial; mutant; novel; pathogen; programs; thymocyte

DESCRIPTION (provided by applicant): Project summary NKT cells are a conserved population of CD Id-restricted innate-like lymphocytes with a hybrid NK/T phenotype. They critically regulate a broad range of disease conditions by releasing Th1 or Th2 cytokines and chemokines upon interactions with DC, macrophages or B cells. The dual specificity of their semi- invariant Va14-Ja18 (Va24-Ja18 in humans) TCR for the self glycosphingolipid iGb3 and for microbial a- glycosylceramides underlies important roles in infectious diseases. In particular NKT cells are essential for defense against alpha-proteobacteria, including some Rickettsiales that are recognized agents of emerging infectious diseases. NKT cells also exert immunoregulation of some primary or transplanted cancers and regulate various autoimmune and inflammatory diseases. The overarching goal of this project is to understand the developmental steps of the NKT cell lineage and the mechanisms underlying its commitment and differentiation. Our previous work identified the self glycosphingolipid iGb3 as a natural ligand of NKT cells and demonstrated the critical importance of early interactions between NKT thymic precursors and CDId-expressing cortical CD4+CD8+ thymocytes. The specific aims will test the hypothesis that !Gb3 is the thymic ligand driving selection by measuring iGb3 expression in the thymus and defining the iGb3-specific TCR Vp repertoire (SA#1), develop a conditional iGb3 synthase mutant mouse (SA#2), test the role of iGb3 and other ligands at different stages of NKT cell development (SA#3) and test the hypothesis that SLAM family members provide the elusive second signal required for NKT development (SA#4). Relevance NKT lymphocytes represent an essential component of immunity against pathogens associated with emerging infectious diseases, such as Rickettsiales. There are marked individual variations in NKT cell frequency and function in the human population and in individual mouse strains. Thus, investigating the basic mechanisms underlying NKT cell development may be important not only to enhance our general knowledge of lymphocyte development, but also for understanding susceptibility to some of the emerging infectious diseases.

描述（由申请人提供）：项目摘要NKT细胞是具有混合NK/T表型的CD ID限制性淋巴细胞的保守群体。他们通过与DC，巨噬细胞或B细胞相互作用后释放Th1或Th2细胞因子和趋化因子来严格调节广泛的疾病状况。其半不变的VA14-JA18（人类中VA24-JA18）TCR的双重特异性对于自糖脂脂IGB3和微生物A-甘油基酶的双重特异性是感染疾病中重要作用的。尤其是NKT细胞对于防御α-蛋白细菌的防御至关重要，其中包括一些被公认的新兴传染病药物的立克。 NKT细胞还施加一些原发性或移植癌症的免疫调节，并调节各种自身免疫性和炎症性疾病。该项目的总体目标是了解NKT细胞谱系的发展步骤以及其承诺和差异化的机制。我们以前的工作将自糖叠脂Igb3确定为NKT细胞的天然配体，并证明了NKT胸腺前体和表达CDID的皮质CD4+ CD4+ CD8+胸腺细胞之间早期相互作用的重要性。具体目的将检验以下假说：GB3是通过测量胸腺中的IgB3表达并定义IGB3特异性TCR VP曲目（SA＃1），发展有条件的IGB3合成小鼠（SA＃2），测试IGB3和其他元单元的角色（SA），在不同的cell seption（SA）的角色（SA）中，在不同的Stage（SA）中，在不同的stage（SA）中，在不同的stage（SA）中，在不同的stage（SA）中，该假设是n.大满贯的家庭成员提供了NKT开发所需的难以捉摸的第二个信号（SA＃4）。相关性NKT淋巴细胞代表了免疫的重要组成部分，以抵抗与新兴的传染病相关的病原体，例如立克西亚氏菌。 NKT细胞频率和功能在人群和单个小鼠菌株中存在明显的变化。因此，研究NKT细胞发育的基本机制不仅对我们对淋巴细胞发育的一般知识的了解，而且对于了解某些新兴的传染病的易感性而言也可能很重要。