Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity

Abstract

Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4CD8 (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin‐23 minicircles in mice

“…To achieve the desired ear phenotype in these strains, it is likely that higher doses of IL‐23 MC would be required. To this end, another group injected 8 μg of IL‐23 MC to C57BL/6 mice to induce ear skin inflammation …”

“…This methodology has been used to investigate IL‐23 associated bone and joint pathology, and it was also noted to cause histological skin thickening on day 35 following administration of 3 μg IL‐23 MC to B10.RIII mice . Another group administrated 8 μg of IL‐23 MC to C57BL/6 mice and induced a significant increase in IL‐23/IL‐17 pathway genes/proteins as well as histological psoriasis‐like scores on day 9, which were reduced by an ROR γ T antagonist . Hydrodynamic delivery of 8 μg IL‐17 MC has also been shown to cause skin inflammation in C57BL/6 mice 7 weeks post‐transfection .…”

“…Studies have reported that sustained levels of circulating IL‐23 over 2–4 weeks following minicircle injection result in gastrointestinal inflammation, while extended evaluation over 2–4 months demonstrated significant bone and joint damage in animals . Similar to the IL‐23 ear injection model, skin inflammation has also been reported following the hydrodynamic administration of IL‐23 MC, but has not been extensively characterized …”

Small-Molecule RORγt Antagonists: One Stone Kills Two Birds

“…Cua and colleagues recently reported that pharmacological inhibition of RORγt by allosteric RORγt antagonists, MRL-871 or MRL-248 (structurally similar to MRL-871 but with improved in vivo pharmacodynamics) resulted in rapid DP thymocyte apoptosis within 3 days and immediate changes in gene expression within 2 hours of drug treatment 8 . Through RNA-Seq analysis of changes in gene expression in DP cells shortly after RORγt inhibition (2 hr) or with RORγt-overexpression, the authors identified 33 genes, including Bcl-x L , Plxnd1 and Sla , that are known to be involved in cell apoptosis and survival, cell migration and positive selection, respectively.…”

“…Interestingly, RORγt inhibition resulted in reduced frequency of myelin oligodendrocyte glycoprotein (MOG)-specific “self-reactive” CD4 + T cells in approximately half of the RORγt antagonist-treated mice 8 . Consequently, RORγt antagonist pre-treatment delayed the autoimmune progression in the experimental autoimmune encephalomyelitis (EAE) model induced by MOG immunization, even though the RORγt antagonist was no longer present during the course of disease induction.…”