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

肝受体同源物-1（LRH-1/NR 5A 2）是一种核受体和转录因子，主要在内胚层来源的组织中表达，在那里它调节发育、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，它在T淋巴细胞中关键地调节增殖，分化和效应功能。因此，LRH-1缺陷型T细胞表现出强烈的减少诱导保护性免疫应答，以及T细胞介导的免疫病理学。有趣的是，T细胞的活化似乎不受LRH-1基因缺失的影响。因此，LRH-1缺陷型T细胞显示出各种活化标志物的正常上调，并产生大量高于野生型对应物的特异性细胞因子，表明强烈极化和偏向的T细胞分化。具体而言，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、Stat 4和GATA 3）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细胞毒性1和2细胞，以及相关的免疫反应。此外，我们将研究在炎症性肠病小鼠模型中抑制T细胞中LRH-1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，并将进一步确定LRH-1作为治疗T细胞介导的免疫病理学的治疗靶点。

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.