Ror Gamma T And Ror Alpha Signature Genes In Human Th17 Cells

ROR gamma t and ROR alpha are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although ROR gamma t signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORa signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. ROR gamma t and ROR alpha signature genes were identified in these Th17 cells treated with specific siRNAs to knock down ROR gamma t or ROR alpha expression. We have generated selective small molecule ROR gamma t modulators and they were also utilized as pharmacological tools in ROR gamma t signature gene identification. Our results showed that ROR gamma t controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by ROR alpha as well albeit a weaker influence. Key Th17 genes including IL -17A, IL -17F, IL -23R, CCL20 and CCR6 were shown to be regulated by both ROR gamma t and ROR alpha. Our results demonstrated an overlapping role of ROR gamma t and ROR alpha in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. ROR gamma t as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORa could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate ROR gamma t or ROR alpha activities in patients.