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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 不变的自然杀伤T（iNKT）细胞包括一种新的调节性淋巴细胞亚群，其对感染性疾病、自身免疫、耐受诱导和肿瘤免疫学具有深远影响。我们研究的长期目标是了解iNKT细胞对其CDld结合的特异性的基本基础。 配体。所有人iNKT细胞都表达由不变的Va24Jo.18 α链与连接上不同的Va24Jo.18 β链配对组成的不寻常的T细胞受体。几乎所有的iNKT细胞都被半乳糖神经酰胺（aGalCer）激活，这是一种在脊椎动物中没有发现的合成鞘糖脂。哺乳动物中天然活化配体的身份仍然难以捉摸。我们将检验以下假设：人活化内源性CD Id配体是与aGalCer反应性iNKT TCR形成重叠但不同的相互作用的鞘糖脂的异质集合。这一假设是基于以下观察： iNKT细胞可以识别组织特异性配体，并且虽然所有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的情况下被激活。推测这些后者iNKT细胞能够识别aGalCer和未鉴定的天然活化配体。来测试我们 假设我们将：i）表征半不变TCR α和β链对天然和合成CD Id配体的iNKT细胞识别的贡献，和ii）定义用于形成天然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谱上发挥其作用的能力使其成为免疫治疗的理想靶标。本提案中的实验将提供iNKT TCR与其CDld结合配体的基本相互作用的详细解释，这对于合理设计此类疗法是必要的。

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.