Molecular Recognition of Ligand by the Gamma Delta T Cell Receptor

描述(由申请人提供)：？？T细胞是机体对感染性疾病、癌症和自身免疫反应的重要组成部分，但其通过T细胞受体(TCR)检测抗原的生化机制尚不清楚。尤其是在人类中，？？T细胞配体仍然含糊不清，其作用也不明确。T细胞与健康和疾病。因此，这项建议的长期目标是了解？的功能、生化和结构机制。TCR配体结合以及这一结合事件如何区分健康组织和不健康组织。我们在最初的资助期取得了相当大的进展，我们的工作总共发表了五篇论文，发表在公认的期刊(NAT)上。免疫、免疫、PNAS、JBC和EMBO)。我们目前的提案旨在扩大我们在？？方面的工作。T细胞对一种新发现的人类相互作用的识别，即脂类分子CD1d的识别。在与阿尔伯特·本德拉克教授的合作下，我们一直在描述人类V1？？对CD1d有反应的T细胞产生脂硫脂。基于我们的初步数据，我们提出了三个目标，重点是揭示这种相互作用在人类免疫和疾病中的作用。目标1：“人类CD1分子特异性T细胞群体的特征”，旨在扩大我们对这一群体身份的有限知识。我们将调查这些细胞在不同的供体池中的频率，并从分子和功能两个方面对它们进行表征。这一目标还将重点放在这些细胞与其他脂质抗原发生交叉反应的可能性上，以确定分子模仿是否在它们的反应中发挥作用。目标2，《T细胞受体与CD1d/脂结合的分子机制的研究》，将重点描述T细胞受体与CD1d/脂之间的相互作用。这些细胞表达的TCRs和CD1d/硫脂。我们将利用蛋白质生物化学、生物物理学和X射线结晶学来阐明？？TCR识别CD1d/硫脂。这将是为数不多的分子特征之一？？TCR/配体相互作用，将极大地促进我们对？？的理解。T细胞识别。我们还将通过生化方法筛选其他CD1d/硫脂的特异性？？T细胞在疾病中的作用，即多发性硬化症。会不会暴露出这些硫脂反应细胞在高度衰弱的自身免疫性疾病中的作用？为了在多个硬化斑块中发现高频率的T细胞，我们试图调查硫脂反应性是否在疾病状态的启动或进展中发挥作用。T细胞既可以是促炎细胞，也可以是调节性细胞，因此我们试图了解这些细胞在多发性硬化症中扮演的角色，如果有的话，这些目的将开始解开？？T细胞在人类免疫生物学中的作用，包括在细胞和分子水平上。由于人们对这些细胞知之甚少，这里提出的研究将从根本上提高我们对这些细胞所看到的东西的理解，并最终促进这些细胞在人类免疫反应中的作用。脂类抗原，直接补充我们的脂类筛选在目标1。目标3，“确定的作用

DESCRIPTION (provided by applicant): ?? T cells constitute an important component of the immune response against infectious agents, cancer and auto-immunity yet the biochemical mechanisms by which they detect antigen through their T cell receptor (TCR) remain unclear. In humans, in particular, the nature of ?? T cell ligands remains ambiguous, as is the role of ?? T cells in health and disease. Thus, the long-term goal of this proposal is to understand the functional, biochemical and structural mechanisms of ?? TCR ligand engagement and how this binding event discriminates between healthy and unhealthy tissue. We made considerable progress in our initial funding period, with five total publications resulting from our work, published in well-recognized journals (Nat. Immunol., Immunity, PNAS, JBC and EMBO). Our current proposal seeks to extend our work on ?? T cell recognition to a newly discovered human interaction, that of the lipid presenting, MHC-like molecule CD1d. In collaboration with Prof. Albert Bendelac, we have been characterizing a population of human V¿1+ ?? T cells that respond to CD1d presenting the lipid sulfatide. Based on our preliminary data, we propose three aims focused on unraveling the function of this interaction in human immunity and disease. Aim 1: "Characterization of a human ?? T cell population specific for CD1 molecules.", seeks to expand our limited knowledge of the identity of this population. We will investigate the frequency of these cells in a diverse donor pool and characterize them both molecularly and functionally. This aim will also focus on the potential for these cells to be cross-reactive with other lipid antigens to identify whether molecular mimicry plays a role in their reactivity. Aim 2, "Elucidatio of the molecular mechanisms by which ?? TCRs bind to CD1d/lipids.", will focus on characterizing the interaction between the ?? TCRs expressed by these cells and CD1d/sulfatide. We will use protein biochemistry, biophysics and x-ray crystallography to elucidate the molecular mechanisms by which the ?? TCR recognizes CD1d/sulfatide. This will represent one of the few molecularly characterized ?? TCR/ligand interactions and will significantly advance our understanding of ?? T cell recognition. We will also biochemically screen for other CD1d/sulfatide specific ?? T cells in disease, i.e. multiple sclerosis.", will expore the role of these sulfatide-reactive cells in the highly debilitating auto-immune disease, MS. Because V¿1+ ?? T cells are found at high frequencies within multiple sclerotic plaques, we seek to investigate whether sulfatide reactivity may be playing a role in the initiation or progression of the disease state. ??T cells can be either pro-inflammatory or regulatory, therefore we seek to understand which role these cells play, if any, in MS. Together, these aims will begin to unravel the mystery of ?? T cells in human immunobiology, both at the cellular and molecular levels. Because so little is known about these cells, the studies proposed here will fundamentally advance our understanding of what these cells see and, ultimately what these cells do in the human immune response. lipid antigens, directly complementary to our lipid screen in Aim 1. Aim 3, "Determine the role of