Altered Glycolipid Ligands for Va14i NKT cells

Va14i NKT 细胞的糖脂配体发生改变

• 批准号: 6922033
• 负责人: BARBARA A SULLIVAN
• 金额: $ 4.83万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922033
• 关键词: CD1 molecule; T cell receptor; antigens; biological signal transduction; cell proliferation; cellular immunity; cytokine; gene expression; genetically modified animals; glycolipids; helper T lymphocyte; immunopharmacology; inhibitor /antagonist; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation; ligands; natural killer cells; postdoctoral investigator; protein tyrosine kinase; receptor binding; stimulant /agonist; surface plasmon resonance; tissue /cell culture

DESCRIPTION (provided by applicant): Va14i NKT cells are a lymphocyte population that express an invariant Va14-Ja18 T cell antigen receptor (TCR). These cells are reactive to the CD1d (a nonclassical class I antigen presenting molecule) when CD1d binds the marine sponge-derived glycolipid a-galactosyl-ceramide (aGalCer). When activated, Va14i cells rapidly produce large amounts of IFNg and IL-4. In the proposed experiments, we will identify novel lipoglycan antigens that can stimulate Va14i NKT cells in different ways, including antagonists and antigens that alter the pattern of NKT cell cytokine production. We will determine the affinity of the interaction between the Va14i TCR and CD1 when bound to glycolipid variants and determine if the hierarchy of affinities is related to antigenic potency and cytokine profile. We will also test the physiologic consequence of differential signal strength in Va14i T cell development via antigenic challenge of mature Va14i T cells by altering the expression of fyn or Ick tyrosine kinases. The proposed experiments will provide strategies for the augmentation and regulation of this important subset of T lymphocytes.

描述（由申请人提供）：Va14i NKT细胞是一种淋巴细胞群，表达不变的Va14-Ja18 T细胞抗原受体（TCR）。当CD1d结合海绵体来源的糖脂a-半乳糖神经酰胺（aGalCer）时，这些细胞对CD1d（一种非经典I类抗原呈递分子）产生反应。激活后，Va14i细胞迅速产生大量IFNg和IL-4。在拟议的实验中，我们将鉴定能够以不同方式刺激Va14i NKT细胞的新型脂聚糖抗原，包括拮抗剂和改变NKT细胞细胞因子产生模式的抗原。我们将确定Va14i TCR和CD1与糖脂变异体结合时相互作用的亲和力，并确定亲和性等级是否与抗原效力和细胞因子谱有关。我们还将通过改变fyn或Ick酪氨酸激酶的表达，对成熟的Va14i T细胞进行抗原挑战，测试不同信号强度在Va14i T细胞发育中的生理后果。所提出的实验将为增强和调节T淋巴细胞的这一重要亚群提供策略。