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

• Applicant: Professor Dr. Thomas Brunner
• Subject Area: Immunology ; Pharmacology
• Term: since 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236581945

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.

• DFG Programme: Research Grants