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.