Harnessing NKT Cell Activation by Glycolipids

利用糖脂激活 NKT 细胞

• 批准号: 7937770
• 负责人: Amy Howell
• 金额: $ 26.78万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937770
• 关键词: Affinity; Anti-Infective Agents; Antigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bacterial Infections; Binding; Biological Assay; C-glycoside; CD8B1 gene; Cells; Ceramides; Chemistry; Collaborations; Colorado; Communicable Diseases; Complex; Dendritic Cells; Development; Epitopes; Funding; Galactosylceramides; Glycolipids; Glycosphingolipids; Goals; Human; Hydrogen Bonding; Hypersensitivity; Immune response; Immune system; Immunologist; Immunology; Infection; Institutes; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-4; Investigation; KRN7000; Length; Ligands; Lupus; Malignant Neoplasms; Mammals; Mediating; Methods; Modification; Multiple Sclerosis; Mus; Natural Killer Cells; Nature; Outcome; Oxygen; Pathway interactions; Photoaffinity Labels; Positioning Attribute; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporting; Research; Role; Structure; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Universities; Viral; analog; antigen processing; base; cell type; cofactor; cytokine; design; immunoregulation; in vivo; killer T cell; medical schools; neutrophil; pathogen; prevent; professor; response; sugar; tumor; tumor progression

Natural Killer T (NKT) cells are potent regulatory T cells that have been shown to be intimately involved in the response to infection and tumor progression. There is also strong evidence that NKT cells may regulate the immune system in such a way as to prevent autoimmunity. Harnessing this activation of NKT cells may provide new therapies for viral and bacterial infections, for cancer and for a range of autoimmune conditions, such as Type I diabetes, multiple sclerosis and lupus. A little more than a decade ago it was revealed that glycolipids, particularly )-galactosylceramides ()- GalCers), could activate NKT cells by serving as ligands to a newly recognized class of antigen presenting proteins, CD1d. For the last five years our lab has designed and synthesized glycosyl ceramides that vary in the ceramide and sugar epitopes in order to probe the role of both regions. In collaboration with immunologists and physical chemists and analytical chemists we propose to continue to investigate the role of glycolipid structure in CD1d mediated immunomodulation with the following goals: 1) )-GalCers with N-anomeric replacements will be synthesized for comparison to the structurally related, but biologically distinct, O-, C- and S-)-GalCers; 2) A set of )-GalCers has been designed and is being synthesized to test the hypothesis that compounds that require antigen processing can be used to induce high levels of Th1 cytokines, which are believed to be responsible for the anti-infective/anti-cancer activities of glycolipids; 3) A recent x-ray report of a ternary complex of )-GalCer/CD1d/NKT T cell receptor will be used to investigate if the saccharide moiety can be used to influence cytokine profiles and/or enhance NKT cell expansion in humans; 4) An MS method for determining anomeric ratios of glycolipids will be developed and used to evaluate the presence of low levels of unwanted anomers.

自然杀伤T（NKT）细胞是有效的调节性T细胞，已被证明是 密切参与对感染和肿瘤进展的反应。还有 强有力的证据表明，NKT细胞可以调节免疫系统的方式， 防止自身免疫。利用NKT细胞的这种激活可以提供新的 治疗病毒和细菌感染，癌症和一系列自身免疫性疾病 这些疾病包括I型糖尿病、多发性硬化症和狼疮。一个多 十年前，人们发现糖脂，特别是半乳糖神经酰胺（）- GalCers），可以通过作为一类新认识的配体激活NKT细胞， 抗原呈递蛋白CD 1d。在过去的五年里，我们的实验室设计并 合成的糖基神经酰胺，其在神经酰胺和糖表位上不同， 探索这两个区域的作用。与免疫学家和物理化学家合作， 和分析化学家，我们建议继续研究糖脂的作用 CD 1d介导的免疫调节中的结构，具有以下目标：1））-GalCers 将合成具有N-异头取代物的化合物，以与结构上的 相关，但生物学上不同的O-，C-和S-）-GalCers; 2）一组）-GalCers已经被 设计和合成的目的是为了测试一种假设， 抗原处理可用于诱导高水平的Th 1细胞因子， 被认为负责糖脂的抗感染/抗癌活性; 3）A 最近X射线报道的）-GalCer/CD 1d/NKT T细胞受体的三元复合物将 用于研究糖部分是否可用于影响细胞因子谱 和/或增强人的NKT细胞扩增; 4）用于确定 将开发糖脂的端基异构体比率，并用于评价 低水平的不需要的端基异构体。

项目成果

Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens.

• DOI: 10.1038/ncomms10570
• 发表时间: 2016-02-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Le Nours J;Praveena T;Pellicci DG;Gherardin NA;Ross FJ;Lim RT;Besra GS;Keshipeddy S;Richardson SK;Howell AR;Gras S;Godfrey DI;Rossjohn J;Uldrich AP
• 通讯作者: Uldrich AP