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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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CDd结合的iNKT细胞特异性的基本基础。 配体(S)。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。这一假设是基于观察到的 INKT细胞可以识别组织特异性的配体，虽然所有的iNKT细胞都被aGalCer激活，但一些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。测试我们的 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CDd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.