ANTIGEN RECOGNITION BY GAMMA DELTA T CELLS

描述（改编自研究者摘要）：T细胞分裂 根据其ab或gd T细胞抗原的表达分为两个亚群 受体。 由于gd T细胞在患者体内扩增， 感染（高达外周血中所有T细胞的50%），它们是 可能与人类对感染的免疫力有关。 此外，鼠gd T细胞在对结核分枝杆菌的免疫中起关键作用， 缺乏gd T细胞的小鼠死于感染。 Gd T细胞也可以是 在自身免疫中很重要，因为它们在患有 某些自身免疫性疾病 支持这一假设的是小鼠 狼疮、自身免疫性糖尿病和胶原诱导的关节炎的模型，其中 gd T细胞发挥限制自身免疫ab T细胞应答的调节作用。 然而，激活这些调节性gd T细胞的抗原并没有 并且只有少数几个被gd T细胞识别的抗原的例子 已经被分子定义了。 最近，调查人员发现， 人gd T细胞的主要亚群被葡萄球菌刺激， 超抗原、SEA和非肽异戊烯基焦磷酸化合物， 异戊烯基焦磷酸 异戊烯基焦磷酸盐是重要的前体 类异戊二烯化合物是由细菌和人类制造的， 代表潜在的外来抗原和自身抗原， 激活免疫或自身免疫gd T细胞。 Gd T细胞识别这些 非肽抗原是由Vg2Vd2TCR介导的，并利用了一种新的 不涉及已知抗原的细胞外呈递途径 呈现分子。 研究者建议进一步定义gd TCR的识别， 确定其功能意义。 在目标1中，Vg2Vd2 TCR结合至 将测量异戊烯焦磷酸抗原和SEA超抗原。 在目的2中，非肽抗原的抗原呈递分子将 通过表征抗原呈递细胞蛋白来鉴定， 与焦磷酸法呢酯的光亲和类似物或与mAb反应。 在目标3中，细菌262和276的结构和功能相关性 道尔顿非结合和核苷酸结合的异戊烯焦磷酸抗原 将被确定。 在目的4中，研究了Vg2Vd2+ T细胞在体内免疫中的作用。 恒河猴对卡介苗感染免疫应答 将对动物模型进行评价。 这些基础研究将提供见解 研究人gd T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.