Molecular Recognition of Ligand by the Gamma Delta T Cell Receptor

描述（由申请人提供）：？？T细胞是对抗感染因子、癌症和自身免疫的免疫应答的重要组成部分，但它们通过T细胞受体（TCR）检测抗原的生化机制尚不清楚。尤其是在人类身上，？？T细胞配体的作用仍然不明确。T细胞在健康和疾病中的作用因此，本提案的长期目标是了解？？的功能、生化和结构机制。TCR配体结合以及这种结合事件如何区分健康和不健康组织。在最初的资助期内，我们取得了相当大的进展，我们的工作共发表了五篇论文，发表在知名期刊上（Nat. Immunol.）。， Immunity， PNAS， JBC和EMBO)。我们目前的建议是将我们的工作扩展到？？T细胞识别一种新发现的人类相互作用，即脂质呈递，mhc样分子CD1d。在与Albert Bendelac教授的合作下，我们一直在描述人类V¿1+ ?？对CD1d有反应的T细胞呈现脂质硫脂。根据我们的初步数据，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：“描述一个人？？”CD1分子特异性T细胞群”，试图扩大我们对这一群体身份的有限认识。我们将研究这些细胞在不同供体池中的频率，并从分子和功能上对它们进行表征。这一目标还将关注这些细胞与其他脂质抗原交叉反应的潜力，以确定分子模仿是否在其反应性中起作用。目标2：“分子机制的阐明？？”TCRs结合CD1d/脂质”，将重点描述？？这些细胞和CD1d/硫脂表达的TCRs。我们将使用蛋白质生物化学，生物物理学和x射线晶体学来阐明？？TCR识别CD1d/硫脂。这将代表为数不多的具有分子特征的？？TCR/配体相互作用，并将显著促进我们对？？T细胞识别。我们还将生化筛选其他CD1d/硫脂特异性？？T细胞在疾病，即多发性硬化症中的作用”，将探索这些硫脂反应细胞在高度衰弱的自身免疫性疾病ms中的作用。T细胞在多发性硬化斑块中发现频率很高，我们试图研究硫脂反应性是否可能在疾病状态的开始或进展中发挥作用。?？T细胞既可以促炎也可以调节，因此我们试图了解这些细胞在多发性硬化症中发挥的作用，如果有的话。总之，这些目标将开始解开？？T细胞在人体免疫生物学中的作用，包括细胞和分子水平。由于对这些细胞知之甚少，这里提出的研究将从根本上推进我们对这些细胞所看到的以及最终这些细胞在人类免疫反应中的作用的理解。脂质抗原，直接补充我们在Aim 1中的脂质筛选。目标3，“确定……的角色。

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