Analysis of Human NKT cell auto-antigens

描述（由申请人提供）：NKT细胞是一群调节性T细胞，已知其能够有效调节免疫应答。控制NKT细胞活化的抗原是由CD 1d分子呈递的脂质和糖脂。NKT细胞的一个显著特征是许多对自身抗原具有自身反应性。这使得它们即使在没有外来抗原攻击的情况下也被激活，并且可能对其内源性免疫调节作用至关重要。被人类NKT细胞识别的自身抗原尚未被鉴定，并且关于它们的呈递是如何被调节的知之甚少。在这里，我们将：i）表征由人CD 1d分子呈递的内源性配体，并分析哪些配体对NKT细胞具有抗原性; ii）对我们的初步结果进行跟踪，该结果表明在炎症条件下产生的称为溶血磷脂酰胆碱（LPC）的细胞间脂质信使是可以被许多人NKT细胞识别的自身抗原; iii）研究CD 1d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，这些脂质特征对于与人CD 1d分子结合和NKT细胞识别非常重要，并将探索NKT细胞活化如何通过识别生物活性脂质介质作为自身抗原与更广泛的炎症生理过程联系起来，并将提供关键的见解CD 1d介导的自身抗原呈递的APC调节的机制。公共卫生相关性：NKT细胞是自身反应性调节性T细胞，识别脂质和糖脂作为CD 1d分子呈递的抗原。人NKT细胞识别的自身抗原的分子身份仍然未知。在此补助金中，我们将：i）鉴定由人NKT细胞识别的组成型呈递的细胞配体; ii）研究脂质信使作为推定的可诱导自身抗原，其可将NKT细胞活化与炎症反应直接联系起来;和iii）分析CD 1d对自身抗原呈递的细胞和分子要求。

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.