ANTIGEN RECOGNITION BY GAMMA DELTA T CELLS

描述(改编自调查人员摘要)：T细胞被分离 根据它们的ab或gd T细胞抗原的表达分为两个亚群 感受器。由于gd T细胞在患者体内大量扩增 感染(高达外周血液中所有T细胞的50%)，它们是 可能与人类对感染的免疫力有关。此外，小鼠gd T细胞在结核分枝杆菌免疫中发挥关键作用，因为 缺乏gd T细胞的小鼠会死于感染。GD T细胞也可能是 在自身免疫中很重要，因为它们在患者的组织中扩张 某些自身免疫性疾病。对这一假设的支持来自于小鼠 狼疮、自身免疫性糖尿病和胶原性关节炎的模型，其中 Gd T细胞发挥调节作用，限制自身免疫性ab T细胞反应。 然而，激活这些调节性GdT细胞的抗原并没有 已被鉴定，仅有少数几个gd T细胞识别的抗原 已经从分子上定义了。最近，调查人员发现， 葡萄球菌刺激人类GDT细胞的优势亚群 超抗原、SEA和非肽戊烯基焦磷酸化合物，如 异戊烯基焦磷酸酯。焦磷酸丙酯是必需的前体 对于在细菌和人类中制造的异戊二烯化合物，因此 既代表潜在的外来抗原，也代表可能 激活免疫或自身免疫的gd T细胞。GDT细胞对这些细胞的识别 非肽抗原是由Vg2Vd2 TCR介导的，并利用一种新的 不涉及已知抗原的细胞外递呈途径 呈现分子。 调查人员建议进一步界定德国技术合作与创新委员会的承认，并 确定其功能意义。在目标1中，Vg2Vd2 TCR绑定到 将对焦磷酸戊烯基超抗原和海超抗原进行测定。 在目标2中，非肽抗原的抗原提呈分子将 通过鉴定抗原提呈细胞蛋白来鉴定 与法尼基焦磷酸的光亲和类似物或单抗反应。 在目标3中，细菌262和276的结构和功能相关性 道尔顿非偶联和核苷酸偶联的戊烯基焦磷酸抗原 将会被确定。目的4 Vg2Vd2+T细胞在体内的作用 恒河猴对牛分支杆菌卡介苗感染的免疫应答 将对动物模型进行评估。这些基础研究将提供深入的见解 探讨人类GdT细胞识别抗原的机制 有助于阐明它们在免疫和自身免疫中的作用。

DESCRIPTION (Adapted from Investigator's abstract): T-cells are divided into two subsets based on their expression of ab or gd T-cell antigen receptors. Since gd T-cells expand in patients during a number of infections (up to 50% of all T-cells in the peripheral blood), they are likely to be involved in human immunity to infection. Moreover, murine gd T-cells play critical roles in immunity to Mycobacterium tuberculosis since mice lacking gd T-cells succumb to infection. Gd T-cells may also be important in autoimmunity since they expand in the tissues of patients with certain autoimmune diseases. Support for this hypothesis comes from murine models for lupus, autoimmune diabetes, and collagen-induced arthritis, where gd T-cells play regulatory roles limiting autoimmune ab T-cell responses. However, the antigens that activate these regulatory gd T-cells have not been identified and only a few examples of antigens recognized by gd T-cells have been molecularly defined. Recently, the investigator found that the predominant subset of human gd T-cells is stimulated by the staphylococcal superantigen, SEA, and by nonpeptide prenyl pyrophosphate compounds such as isopentenyl pyrophosphate. Prenyl pyrophosphates are essential precursors for isoprenoid compounds that are made in bacteria and man and thus represent both potential foreign as well as self antigens that could activate immune or autoimmune gd T-cells. Gd T-cell recognition of these nonpeptide antigens is mediated by the Vg2Vd2 TCR and utilizes a novel extracellular presentation pathway that does not involve known antigen presenting molecules. The investigators propose to further define recognition by the gd TCR and determine its functional significance. In Aim 1 Vg2Vd2 TCR binding to the prenyl pyrophosphate antigens and to the SEA superantigen will be measured. In Aim 2, the antigen presenting molecule for the nonpeptide antigens will be identified by characterizing the antigen presenting cell protein that reacts with a photoaffinity analog of farnesyl pyrophosphate or with mAbs. In Aim 3, the structural and functional relevance of bacterial 262 and 276 Dalton unconjugated and nucleotide-conjugated prenyl pyrophosphate antigens will be determined. In Aim 4 the role of Vg2Vd2+ T-cells in the in vivo immune response to Mycobacterium bovis BCG infections in rhesus monkey animal model will be evaluated. These basic studies will provide insights into the mechanisms of antigen recognition by human gd T-cells and should help clarify their role in immunity and autoimmunity.