VERMONT COBRE: PROJ 1: INKT CELL ACTIVATION BY CD ID & ITS LIGANDS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。不变自然杀伤T细胞(INKT)是一类新的调节性淋巴细胞亚群，在感染性疾病、自身免疫、耐受诱导和肿瘤免疫等方面具有重要作用。我们研究的长期目标是了解控制其CDLD结合配体(S)的iNKT细胞特异性的基本基础。所有的人iNKT细胞都表达一种不同寻常的T细胞受体，该受体由一个不变的Va24Jo.18α链和一个连接多样的Vpllβ链组成。几乎所有的iNKT细胞都被半乳糖基神经酰胺(AGalCer)激活，这是一种合成的神经鞘糖脂，在脊椎动物中没有发现。哺乳动物中天然激活配体的身份仍然难以捉摸。我们将测试这样的假设，即人类激活的内源性CD ID配体是一组不同的糖鞘糖脂，它们与GalCer反应的iNKT TCRs形成重叠但不同的相互作用。这一假说是基于以下观察结果：iNKT细胞可以识别组织特异性配体，虽然所有iNKT细胞都被aGalCer激活，但一些但不是全部iNKT细胞在存在和不存在aGalCcr的情况下都被激活。推测这些iNKT细胞能够识别aGalCer和未知的天然激活配体。为了验证我们的假设，我们将：i)表征半不变的TCRα和β链对iNKT细胞识别天然和合成CD ID配体的贡献，以及ii)确定用于形成天然CD ID配体和/或其前体的糖基神经酰胺的生物合成途径和异质性。INKT细胞在广泛的免疫学范围内发挥作用的能力使它们成为免疫治疗的理想靶点。这项建议中的实验将详细揭示iNKT TCR与其CDLD结合配体的基本相互作用，这是合理设计此类疗法所必需的

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Invariant natural killer T (iNKT) cells comprise a novel subset of regulatory lymphocytes that has a profound effect on infectious disease, autoimmunity, tolerance induction, and tumor immunology. The long term goal of our research is to understand the fundamental basis governing iNKT cell specificity for its CDld-bound ligand(s). All human iNKT cells express an unusual T cell receptor consisting of an invariant Va24Jo.l 8 alpha chain paired with ajunctionally diverse Vpll beta chain. Nearly all iNKT cells are activated by ¿- galactosylceramide (aGalCer), a synthetic glycosphingolipid that is not found in vertebrates. The identity of natural activating ligands in mammals has remained elusive. We will test the hypothesis that the human activating endogenous CD Id ligands are a heterogeneous set of glycosphingolipids that form overlapping but distinct interactions with aGalCer-reactive iNKT TCRs. This hypothesis is based on the observations that iNKT cells can recognize tissue-specific ligands, and that while all iNKT cells arc activated by aGalCer, some, but not all, iNKT cells are activated in the presence and in the absence of aGalCcr. Presumably these latter iNKT cells are able to recognize both aGalCer and unidentified natural activating ligands. To test our hypothesis we will: i) Characterize the contribution of the semi-invariant TCR alpha and beta chains to iNKT cell recognition of natural and synthetic CD Id ligands, and ii) define biosynthetic pathways and the heterogeneity of glycosylceramides used in the formation of natural CDld ligands and/or their precursors. The ability of iNKT cells to exert their effects over a wide irnmunological spectrum makes them ideal targets for immunotherapy. The experiments in this proposal will provide the detailed undcrstt.nding of the fundamental interactions of iNKT TCRs with their CDld-bound ligands necessary for the rational design of such therapies