RORγt and RORα signature genes in human Th17 cells

Abstract

RORγt and RORα 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 RORγt 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 RORα 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. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα 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 RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt 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 RORα 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 RORγt or RORα activities in patients.

Ginkgo biloba extract attenuates the disruption of pro-and anti-inflammatory T-cell balance in peripheral blood of arsenicosis patients

“…RORγt, a transcription factor, is involved in the development and function of Th17 cells [12]. Foxp3 is a master gene responsible for the immune-suppressing activity of Treg cells [32].…”

“…In Th17 cells, RORγt is a master transcription factor, and Foxp3 is a transcription factor for differentiation and function of Treg cells [12,32]. To confirm the imbalance in the ratio of Th17/Treg cells, we determined the relative mRNA levels of specific transcription factors in PBMCs of subjects in the two groups by qRT-PCR.…”

“…Although T helper 17 (Th17) and T regulatory (Treg) cells both differentiate from naïve CD4 + T cells, they are distinct populations that have functionally opposite effects [10]. Th17 cells represent a pro-inflammatory subset that expresses retinoic acid-related orphan receptor γt (RORγt) and is involved in the development of autoimmunity and allergic reactions by producing IL-17 [11,12]; Treg cells express the forkhead/winged helix transcription factor 3 (Foxp3), have an anti-inflammatory role, and maintain tolerance to self-components through direct contact with cells or by releasing anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β1 (TGF-β1) [13,14]. The ratio of Th17/Treg cells regulates immune activities, and Th17/Treg imbalances may provide a basis for understanding the immunological mechanisms that induce and regulate autoimmunity and chronic inflammation [15].…”

T cells and their function in the immune response to viruses

“…The master switch factors for Th17 cells are the transcription factor RORγt/RORC2 (mice/human), RORα, basic leucine zipper transcription factor, ATF-like (BATF), and IRF4 (Ivanov et al, 2006;Unutmaz, 2009). RORγt and RORα control the key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 (Castro et al, 2017). The development of the Th17 phenotype is regulated by RORC2, STAT3 factors and BATF, which are part of a BATF/ Jun/IRF4 pathway (Ciofani et al, 2012;Li et al, 2012).…”

Meta-Analysis of Transcriptomic Variation in T cell Populations Reveals Novel Signatures of Gene Expression and Splicing

“…For example, Th2 cells are enriched for GATA3, GATA3-AS1 and SEMA5A (Zhang et al, 2013a), IL17RB (Wang et al, 2007), AKAP12 (Lund et al, 2007), GATA3, HPGDS (Mitson-Salazar et al, 2016) and PTGDR2 (aka CRTH2). The top ten Th17 reliably expressed genes included ADAM12 (Zhou et al, 2013), COL5A3(Castro et al, 2017), RORC, CCR6, IL1R1(Hu et al, 2011), ABCB1(Ramesh et al, 2014), PLXND1(Guo et al, 2016), and MAP3K4 (Cleret-Buhot et al…”