Investigating the function of gamma-delta T cells

γ - δ T细胞、B细胞和α - β T细胞是在发育过程中对克隆抗原受体进行重排的淋巴细胞。这三种血统在整个进化过程和跨物种中都是保守的。γ - δ T细胞常见于粘膜组织和皮肤。然而，它们的功能仍然只是部分被理解，至少是因为没有严格的功能丧失实验模型适合于研究γ - δ T细胞的功能。TCR δ链敲除小鼠的表型被携带α - β T细胞受体的非常规γ - δ T细胞样细胞所掩盖，这些细胞接管空的γ - δ T细胞壁龛。此外，我们最近发现γ - δ T细胞完全难以通过注射单克隆抗体在体内消耗。因此，在初步工作中，我们建立了一种新的转基因小鼠模型来研究γ - δ T细胞在体内的功能。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的表达将使我们能够在体内免疫反应中可视化γ - δ T细胞。此外，这些小鼠的γ - δ T细胞表达人类白喉毒素受体。由于所有其他小鼠细胞不表达转基因毒素受体，γ - δ T细胞可以通过注射毒素在体内有条件地特异性消融。我们将利用新生成的Tcrd-GDL小鼠在人类疾病的实验模型中探索γ - δ T细胞在体内的功能。我们将进行真菌和细菌感染的实验，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，这个项目的目标是揭示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共享冗余功能的程度。

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.