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Investigating the function of gamma-delta T cells

研究 γ-δ T 细胞的功能

基本信息

批准号：
326018237
负责人：
Professor Dr. Immo Prinz
金额：
--
依托单位：
Institut für Systemimmunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/326018237?language=en
关键词：
Investigating function gamma delta cells

项目摘要

Gamma-delta T cells, B cells and alpha-beta T cells are lymphocytes that rearrange clonal antigen receptors during their development. These three lineages are conserved throughout evolution and across species. Gamma-delta T cells are frequent in mucosal tissues and in skin. However, their function is still only partially understood, not at least because there is no stringent loss-of-function experimental model suited to investigate the function of gamma-delta T cells. The phenotype of TCR delta chain knock-out mice is cloaked by unconventional gamma-delta T cell-like cells bearing alpha-beta T cell receptors that take over empty gamma-delta T cell niches. Furthermore, we recently showed that gamma-delta T cells are fully refractory to in vivo depletion by injection of monoclonal antibodies. In preliminary work, we have therefore generated a novel genetically modified mouse model to investigate the function of gamma-delta T cells in vivo. In these Tcrd-GDL mice, gamma-delta T cell-specific reporter fluorescence and luciferase expression will enable us to visualize gamma-delta T cells during immune responses in vivo. Furthermore, gamma-delta T cells of these mice express the human diphtheria toxin receptor. Because all other mouse cells do not express the transgenic toxin receptor, gamma-delta T cells can be conditionally and specifically ablated in vivo by injection of the toxin. We will employ the newly generated Tcrd-GDL mice to explore the function of gamma-delta T cells in vivo in experimental models for human disease. We will perform experimental fungal and bacterial infections and we will determine the role of gamma-delta T cells in models for psoriasis and wound healing. Furthermore, the Tcrd-GDL system is ideally suited and will be applied to investigate the development, differentiation and regenerative potential of pro-inflammatory effector gamma-delta T cell populations. Overall, the goal of this project is to reveal the specific biologic roles of gamma-delta T cells and to establish how far they might share redundant functions with other innate lymphocyte populations.

γ-δ T细胞、B细胞和α-β T细胞是在其发育过程中重排克隆抗原受体的淋巴细胞。这三个谱系在整个进化过程中和跨物种之间都是保守的。γ-δ T细胞常见于粘膜组织和皮肤中。然而，它们的功能仍然只是部分理解，至少不是因为没有适合研究γ-δ T细胞功能的严格的功能丧失实验模型。TCR δ链敲除小鼠的表型被非常规的γ-δ T细胞样细胞掩盖，这些细胞携带α-β T细胞受体，接管空的γ-δ T细胞小生境。此外，我们最近表明，γ-δ T细胞是完全难治的单克隆抗体注射体内消耗。因此，在初步工作中，我们已经产生了一种新的遗传修饰小鼠模型，以研究体内γ-δ T细胞的功能。在这些Tcrd-GDL小鼠中，γ-δ T细胞特异性报告荧光和荧光素酶表达将使我们能够在体内免疫应答期间可视化γ-δ T细胞。此外，这些小鼠的γ-δ T细胞表达人白喉毒素受体。因为所有其他小鼠细胞不表达转基因毒素受体，所以γ-δ T细胞可以通过注射毒素在体内被条件性和特异性地消融。我们将使用新产生的Tcrd-GDL小鼠来探索γ-δ T细胞在人类疾病实验模型中的体内功能。我们将进行实验性真菌和细菌感染，我们将确定γ-δ T细胞在银屑病和伤口愈合模型中的作用。此外，Tcrd-GDL系统非常适合并将被应用于研究促炎效应γ-δ T细胞群的发育、分化和再生潜力。总的来说，该项目的目标是揭示γ-δ T细胞的特定生物学作用，并确定它们与其他先天淋巴细胞群体共享冗余功能的程度。