Role of the nuclear receptor LRH-1/Nr5a2 in T helper cell differentiation and immunopathology

核受体LRH-1/Nr5a2在T辅助细胞分化和免疫病理学中的作用

• 批准号: 236581945
• 负责人: Professor Dr. Thomas Brunner
• 金额: --
• 依托单位: Lehrstuhl für Biochemische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/236581945?language=en
• 关键词: Role; nuclear; receptor; LRH; Nr5a2

Liver Receptor Homolog-1 (LRH-1/NR5A2) is a nuclear receptor and transcription factor predominantly expressed in tissues of endodermal origin, where is regulates development, metabolism and steroidogenesis. In the past research project, we could, however, demonstrate for the first time LRH-1 expression in T lymphocytes, where it critically regulates proliferation, differentiation and effector functions. Thus, LRH-1-deficient T cells demonstrated a strong reduction in the induction of protective immune responses, as well as T cell-mediated immunopathologies. Interestingly, activation of T cells appears not to be affected by the deletion of the LRH-1 gene. Thus, LRH-1-deficient T cells show normal upregulation of various activation markers, and produced massively higher amounts of specific cytokines than their wild type counterparts, suggesting a strongly polarized and biased T cell differentiation.This research project thus aims at investigating the role of LRH-1 in the differentiation of T cells. Specifically, we will investigate the role of LRH-1 in the transcriptional regulation of transcription factors involved in the differentiation and polarization of T cells, i.e. Tbet, Stat4 and GATA3, and how LRH-1 affects differentiation of T helper 1 and 2, resp. T cytotox 1 and 2 cells, and associated immune responses. Furthermore, we will investigate the therapeutic potential of LRH-1 inhibition in T cells in a mouse model of inflammatory bowel disease. These studies will reveal novel insight on the role of LRH-1 in the transcriptional regulation of T cell differentiation and polarization, and will further define LRH-1 as a therapeutic target in the treatment of T cell-mediated immunopathologies.

肝脏受体同源物-1 (LRH-1/NR5A2) 是一种核受体和转录因子，主要在内胚层起源的组织中表达，调节发育、代谢和类固醇生成。然而，在过去的研究项目中，我们首次证明了 LRH-1 在 T 淋巴细胞中的表达，它对增殖、分化和效应功能具有重要调节作用。因此，LRH-1缺陷的T细胞在保护性免疫反应以及T细胞介导的免疫病理的诱导方面表现出强烈的减少。有趣的是，T 细胞的激活似乎不受 LRH-1 基因删除的影响。因此，LRH-1缺陷的T细胞表现出各种激活标记的正常上调，并产生比野生型对应物高得多的特定细胞因子，表明T细胞分化具有强烈的极化和偏向性。因此，本研究项目旨在研究LRH-1在T细胞分化中的作用。具体来说，我们将研究 LRH-1 在参与 T 细胞分化和极化的转录因子（即 Tbet、Stat4 和 GATA3）的转录调节中的作用，以及 LRH-1 如何影响 T 辅助细胞 1 和 2 的分化。 T 细胞毒素 1 和 2 细胞以及相关的免疫反应。此外，我们将在炎症性肠病小鼠模型中研究 LRH-1 抑制 T 细胞的治疗潜力。这些研究将揭示LRH-1在T细胞分化和极化的转录调节中的作用的新见解，并将进一步将LRH-1定义为治疗T细胞介导的免疫病理学的治疗靶点。