IMMUNOREGULATORY ROLE OF GAMMA DELTA T CELLS IN TB

全球每年死于结核病的人数比其他任何疾病都要多。 具有传染性的人类病原体。根除结核病将需要 开发一种有效的疫苗，这反过来又取决于对 结核病的保护性免疫机制。免疫 对结核分枝杆菌的应答被认为是由T淋巴细胞介导的 识别分枝杆菌抗原的生物。抗原识别是通过以下途径介导的 T细胞受体由α链和β链组成，或由伽马链和β链组成 锁链。尽管Gammadelta T细胞的功能仍不清楚，但 越来越多的证据表明它们参与了免疫反应 分枝杆菌和其他病原微生物。这件事的目的是 建议研究携带Gammadelta T的淋巴细胞的作用 细胞受体在介导抵抗和保护免疫反应中的作用 结核分枝杆菌。我们的具体目标是：1)确定 Gammadelta T细胞及其亚群在组织中的分布 以及患者的血液中的所有结核感染， 采用单、双免疫组织化学染色。Gammadelta T的抗原反应性 将通过测量Gammadelta T的百分比来评估细胞 结核分枝杆菌体外培养后的细胞。2)表征 分枝杆菌抗原和表位被Gammadelta T细胞识别 非霍奇金淋巴瘤患者Gammadelta T细胞系及克隆的建立 结核杆菌感染及其对分枝杆菌的反应性检测 直接或通过T细胞Western印迹技术检测抗原。表位 定义将通过测试Gammadelta T细胞克隆来实现 人工合成的重叠多肽。3)功能能力评估 通过测定Gammadelta T细胞的淋巴因子分泌模式 以及由分枝杆菌抗原触发时的细胞毒能力。4) 伽马基因编码基因多样性程度的测定 和T细胞受体在整个光谱中的增量链 在结核感染和疾病活动部位，使用聚合酶链式反应 扩增相关基因片段。有限的多样性会表明 Gammadelta T细胞识别高度保守的抗原，如热休克 蛋白质。拟议的研究将提供有关基本知识的信息 关于Gammadelta T淋巴细胞在免疫中作用的几个问题 对传染性病原体的反应。

Tuberculosis causes more deaths annually world-wide than any other infectious human pathogen. Eradication of tuberculosis will require development of an effective vaccine, which in turn hinges on understanding the mechanism of protective immunity against tuberculosis. Immune responses to M. tuberculosis are thought to be mediated by T lymphocytes that recognize mycobacterial antigens. Antigen recognition is mediated by T cell receptors composed of alpha and beta chains, or gamma and delta chains. Although the functions of gammadelta T cells remain unknown, there is growing evidence that they are involved in the immune response to mycobacteria and other pathogenic microorganisms. The gaol of this proposal is to investigate the role of lymphocytes bearing gammadelta T cell receptors in mediating resistant and protective immune responses to Mycobacterium tuberculosis. Our specific aims are: 1) Determination of the distribution of gammadelta T cells and their subpopulations in tissue and blood of patients throughout the spectrum of tuberculous infection, using single and double immunostaining. Antigen reactivity of gammadelta T cells will be evaluated by measurement of the percentage of gammadelta T cells after culture in vitro with M. tuberculosis. 2) Characterization of mycobacterial antigens and epitopes recognized by gammadelta T cells by establishing gammadelta T cell lines and clones from patients with tuberculous infection and testing their reactivity to mycobacterial antigens directly or by the T-cell Western blot technique. Epitope definition will be achieved by testing gammadelta T cell clones against synthetic overlapping peptides. 3) Evaluation of the functional capacity of gammadelta T cells by determining their pattern of lymphokine secretion and cytotoxic capacity when triggered by mycobacterial antigens. 4) Determination of the degree of diversity of the genes coding for the gamma and delta chains of the T cell receptor throughout the spectrum of tuberculous infection and at the site of disease activity, using PCR to amplify relevant gene segments. Limited diversity would suggest that gammadelta T cells recognize highly conserved antigens such as heat shock proteins. The studies proposed will provide information on fundamental questions regarding the function of gammadelta T lymphocytes in the immune response to infectious pathogens.