Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Abstract

Retinoic acid-related orphan receptor γT (RORγT) is the orphan nuclear receptor that regulates the development of Th17 cells and the expression of IL-17. The differentiation of Th17 cells is associated with the upregulation of RORγT mRNA, and the mechanisms regulating that process in human cells are not well understood. We investigated the transcriptional regulation of RORγT in a human lymphocytic cell line and Th17 differentiated from naive CD4+ cells from human peripheral blood. A series of experiments, including 5' deletion and in situ mutagenesis analysis of the human RORγT promoter, chromatin immunoprecipitation, and overexpression of selected transcription factors, revealed that the transcription factors upstream stimulatory factor 1 (USF-1) and USF-2 are indispensable for the transcription of RORγT in human lymphocytes. There was also upregulation of USF-1 and USF-2 during the differentiation of Th17 cells from naive CD4+ cells. In this article, we report the first analysis, to our knowledge, of the human RORγT promoter and demonstrate the role of the USF-1 and USF-2 transcription factors in regulating the expression of RORγT in human lymphocytes. Thus, USFs are important for the molecular mechanisms of Th17 differentiation, and possible changes in the expression of USFs might be of interest for inflammatory conditions with a Th17 component. Furthermore, these observations suggest a possible link between metabolic disorders in which the role of glucose-induced USF expression has already been established and autoimmune diseases in which the upregulation of RORγT is frequently detected.