Analysis of Human NKT cell auto-antigens

人类 NKT 细胞自身抗原的分析

• 批准号: 8044075
• 负责人: Jenny E. Gumperz
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044075
• 关键词: Address; Antigen Presentation; Antigens; Autoantigens; Binding; Biology; Cell surface; Cells; Cellular biology; Characteristics; Cleaved cell; Clone Cells; Disease Outcome; Enzymes; Glycolipids; Grant; Human; Human Biology; Human Identifications; Immune response; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lecithin; Ligands; Link; Lipid Binding; Lipids; Mediating; Molecular; Mutagenesis; Pathway interactions; Phospholipase A2; Phospholipase C; Physiological Processes; Population; Process; Property; Protein Isoforms; Regulatory T-Lymphocyte; Role; Site; Testing; Therapeutic Intervention; Transmembrane Domain; autoreactivity; base; extracellular; follow-up; in vivo; insight; lipid mediator; public health relevance; trafficking

DESCRIPTION (provided by applicant): NKT cells are a population of regulatory T cells that is known to be able to potently modulate immune responses. The antigens that control NKT cell activation are lipids and glycolipids presented by CD1d molecules. A remarkable characteristic of NKT cells is that many are autoreactive to self antigens. This allows them to become activated even when there is no foreign antigenic challenge, and may be critical for their endogenous immunoregulatory effects. The auto-antigens recognized by human NKT cells have not been identified, and little is known about how their presentation is regulated. Here we will: i) characterize the endogenous ligands presented by human CD1d molecules, and analyze which ones are antigenic for NKT cells; ii) follow up on our preliminary results, which indicate that an intercellular lipid messenger called lyso- phosphatidylcholine (LPC) that is produced under inflammatory conditions, is a self antigen that can be recognized by many human NKT cells; iii) investigate the cellular and molecular requirements for CD1d-mediated auto-antigen presentation to NKT cells. These studies will provide new information about the lipid characteristics that are important for binding to human CD1d molecules and for recognition by NKT cells, and will explore how NKT cell activation is linked to broader physiological processes of inflammation through recognition of bio-active lipid mediators as self antigens, and will provide critical insights into the mechanisms by which CD1d- mediated auto-antigen presentation is regulated by APCs. PUBLIC HEALTH RELEVANCE: NKT cells are autoreactive regulatory T cells that recognize lipids and glycolipids as antigens presented by CD1d molecules. The molecular identity of the auto-antigens recognized by human NKT cells remains unknown. In this grant we will: i) identify constitutively presented cellular ligands that are recognized by human NKT cells; ii) investigate lipid messengers as putative inducible auto-antigens that may directly link NKT cell activation to inflammatory responses; and iii) analyze cellular and molecular requirements for auto-antigen presentation by CD1d.

描述（由申请人提供）：NKT 细胞是调节性 T 细胞群体，已知能够有效调节免疫反应。控制 NKT 细胞活化的抗原是 CD1d 分子呈递的脂质和糖脂。 NKT 细胞的一个显着特征是许多细胞对自身抗原有自身反应。这使得它们即使在没有外来抗原挑战的情况下也能被激活，并且可能对其内源性免疫调节作用至关重要。人类 NKT 细胞识别的自身抗原尚未被鉴定，并且对其表达的调节方式知之甚少。在这里，我们将： i) 表征人类 CD1d 分子呈递的内源配体，并分析哪些对 NKT 细胞具有抗原性； ii) 跟进我们的初步结果，该结果表明炎症条件下产生的一种称为溶血磷脂酰胆碱（LPC）的细胞间脂质信使是一种可以被许多人类 NKT 细胞识别的自身抗原； iii) 研究 CD1d 介导的自身抗原呈递给 NKT 细胞的细胞和分子要求。这些研究将提供有关脂质特征的新信息，这些特征对于与人类 CD1d 分子结合和 NKT 细胞识别非常重要，并将探讨 NKT 细胞激活如何通过识别生物活性脂质介质与更广泛的炎症生理过程联系起来。自身抗原，并将提供对 CD1d 介导的自身抗原呈递受 APC 调节的机制的重要见解。公共健康相关性：NKT 细胞是自身反应性调节 T 细胞，可将脂质和糖脂识别为 CD1d 分子呈递的抗原。人类 NKT 细胞识别的自身抗原的分子身份仍然未知。在这笔资助中，我们将： i) 识别人类 NKT 细胞识别的组成型细胞配体； ii) 研究脂质信使作为假定的诱导性自身抗原，可能直接将 NKT 细胞激活与炎症反应联系起来； iii) 分析 CD1d 呈递自身抗原的细胞和分子需求。