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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。不变性自然杀伤T细胞（iNKT）是一种新的调节性淋巴细胞亚群，在感染性疾病、自身免疫、耐受性诱导和肿瘤免疫学中具有深远的影响。我们研究的长期目标是了解控制cdld结合配体的iNKT细胞特异性的基本基础。所有人类iNKT细胞都表达一种不寻常的T细胞受体，由不变的Va24Jo组成。l 8 α链与结性多样的Vpll β链配对。几乎所有的iNKT细胞都被半乳糖神经酰胺（aGalCer）激活，这是一种合成的鞘糖脂，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。我们将验证人类激活内源性CD Id配体是一组异质鞘糖脂的假设，这些鞘糖脂与agalcer反应性iNKT tcr形成重叠但不同的相互作用。这一假设是基于观察到iNKT细胞可以识别组织特异性配体，虽然所有的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的情况下被激活。推测这些后一种iNKT细胞能够识别aGalCer和未识别的天然激活配体。为了验证我们的假设，我们将：1)表征半不变的TCR α和β链对iNKT细胞识别天然和合成CDld配体的贡献，2)定义生物合成途径和用于形成天然CDld配体和/或其前体的糖基神经酰胺的异质性。iNKT细胞在广泛的免疫光谱中发挥作用的能力使其成为免疫治疗的理想靶点。本提案中的实验将提供详细的理解。iNKT TCRs与cdld结合配体的基本相互作用的结束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