ROR agonist hampers the proliferation and survival of postactivated CD8+ T cells through the downregulation of cholesterol synthesis-related genes

Abstract

Cholesterol is a major component of the lipid bilayers of cellular membranes. The synthesis of cholesterol is acutely elevated during T-cell activation to support T-cell growth and proliferation. There is a limited understanding of cholesterol metabolism reprogramming during T-cell activation. Retinoic acid receptor-related orphan receptors (RORs) are ligand-activated nuclear receptors that regulate the transcription of target genes. In this study, we demonstrated that the activation of RORs by a synthetic agonist (SR1078) impairs the proliferation and survival of postactivated CD8⁺ T cells. The inhibitory effects of SR1078 on CD8⁺ T-cell proliferation and survival were attributed to cholesterol depletion and downregulated expression of cholesterol metabolism-related genes. The overexpression of RORα or RORγt promoted apoptosis in the postactivated CD8⁺ T cells in vitro. The expression of RORα (but not that of RORγt) was markedly upregulated in the CD8⁺ T cells upon stimulation with an antigen in vivo. The functional deficiency of RORα enhanced CD8⁺ T-cell expansion during the response to bacterial infection. These results suggest that RORs are involved in the regulation of CD8⁺ T-cell-mediated immune response through the regulation of cholesterol metabolism, which can be modulated by a synthetic ROR agonist. The findings of this study can aid in the development of immunotherapeutic methods that target nuclear receptors.

Keywords: Agonist; CD8+ T cells; ROR; cholesterol; nuclear receptor.