Analysis of Human NKT cell auto-antigens

描述（由申请人提供）：NKT细胞是一种已知能够有效调节免疫反应的调节性T细胞群。控制NKT细胞活化的抗原是由CD1d分子呈递的脂质和糖脂质。NKT细胞的一个显著特征是许多细胞对自身抗原具有自体反应性。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，并且对其呈递如何被调节知之甚少。在这里，我们将：i)表征人类CD1d分子呈现的内源性配体，并分析哪些是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细胞间脂质信使lyso-磷脂酰胆碱（LPC）是一种可以被许多人类NKT细胞识别的自身抗原；iii)研究cd1介导的自身抗原向NKT细胞呈递的细胞和分子要求。这些研究将提供关于脂质特性的新信息，这些信息对于与人类CD1d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相关联，并将为CD1d介导的自身抗原呈递由apc调节的机制提供重要见解。公共卫生相关性：NKT细胞是一种自身反应性调节性T细胞，可识别由CD1d分子呈递的脂质和糖脂质抗原。人类NKT细胞识别的自身抗原的分子特性仍然是未知的。在这项资助中，我们将：i)鉴定被人类NKT细胞识别的组成呈递的细胞配体；ii)研究脂质信使作为可能直接将NKT细胞激活与炎症反应联系起来的诱导性自身抗原；iii)分析CD1d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.