2020-04-23T15:21:10+08:002019-05-21|Seminars and Workshops|

Talk title   Disentangling the manifold functions of RORt: a way to target autoimmune diseases
Speaker Dr. Zhiheng HE
Post-doctoral Fellow
Date & Time 6 May 2019 (Mon)
Venue Room G004, E12 Building (University of Macau)
Abstract T helper 17 (TH17) cells are critical for defensive immunity against extracellular bacterial and fungal infection, as well as responsible for autoimmune diseases, including psoriasis, Crohn’s disease, arthritis, and multiple sclerosis. Since differentiation of TH17 cells from naïve CD4+ T cells is dependent on their expression of the transcription factor RORt, RORt has immediately been considered as a prime drug target for the development therapeutic strategies for autoimmune diseases. However, beyond its function in promoting tissue-destructive TH17 cells, RORt also has a fundamental role in homeostasis of the immune system—i.e., thymocyte maturation and the development of defensive TH17 cells. How to specifically target RORtmediated pathology but spare its physical functions in order to develop drugs precisely cure autoimmunity is largely unknown. By using alanine scanning, in vitro differentiation and in vivo ‘knockin’ mutagenesis, I identified several functional motifs from RORt. Based on their functions in T cell maturation, defensive immunity and autoimmunity fundamental, these motifs are divided into three different types: fundamental, peripheral T cell-related and pathology-related motifs. Mice harboring mutations in pathology-related motif of RORt are resistant to autoimmune diseases and have normal T cell development in thymus as well as intact protective immune responses to enteropathogen infections. These studies demonstrate the possibility and importance of genetic dissection of protein functions in order to manipulate transcription factors to specifically control gene expression and cell differentiation and also open the way to generation of drugs precisely targeting RORt-mediated autoimmune diseases.