Analysis of Human NKT cell auto-antigens

人类 NKT 细胞自身抗原的分析

• 批准号: 7803713
• 负责人: Jenny E. Gumperz
• 金额: $ 36.28万
• 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/7803713
• 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细胞的群体，已知能够有效调节免疫反应。控制NKT细胞活化的抗原是CD1D分子提出的脂质和糖脂。 NKT细胞的一个显着特征是许多对自抗原具有自动反应性。即使没有外国抗原挑战，这也可以激活它们，并且可能对内源性免疫调节作用至关重要。尚未鉴定出人类NKT细胞识别的自身抗原，并且对如何调节其表现知之甚少。在这里，我们将：i）表征人CD1D分子呈现的内源性配体，并分析哪些配体是NKT细胞的抗原； ii）跟进我们的初步结果，该结果表明在炎症条件下产生的一个被称为溶菌磷脂酰胆碱（LPC）的细胞间脂质信使是一种自我抗原，可以被许多人类NKT细胞识别。 iii）研究CD1D介导的自身抗原对NKT细胞的细胞和分子需求。这些研究将提供有关脂质特征的新信息，这些信息对于与人CD1D分子的结合以及NKT细胞的识别很重要，并将探讨NKT细胞激活如何与更广泛的炎症生理过程联系起来，通过识别生物活性脂质介体的识别，以自动抗原的介导，并将通过自动介导的介导，并将逐渐通过自动启动，并将其逐渐置于自动启动中，并将CD1置于机械上，该机械学是在CD1中逐渐构成的，该机械学是通过介导的，该机械学阶段 - 该机械学，该机械学是通过介导的，该机械学是介绍的，该机械学是通过介导的，该机械学是在介绍中的。 APC。公共卫生相关性：NKT细胞是自动反应性调节性T细胞，识别脂质和糖脂为CD1D分子呈现的抗原。人NKT细胞识别的自身抗原的分子身份仍然未知。在这笔赠款中，我们将：i）确定由人NKT细胞识别的组成性呈现的细胞配体； ii）研究脂质使者是推定的诱导自身抗原，可能将NKT细胞激活与炎症反应联系起来； iii）通过CD1D分析自身抗原表现的细胞和分子需求。