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.

Inverse Agonist of Retinoid-Related Orphan Receptor-Alpha Prevents Apoptosis and Degeneration in Nucleus Pulposus Cells via Upregulation of YAP

“…Loss of RORα results in progressive, diverse testicular damage and leads to apoptosis, suggesting that RORα knockout promotes apoptosis in the testicle [35]. However, other studies revealed the proapoptosis effect of RORα in different cell types [36,37], suggesting the complexity of RORα in regulating cell senescence and apoptosis. Mediators of Inflammation TNF-α is regarded as one of the most critical factors contributing to IDD's pathogenesis [38,39].…”

The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection

“…Studies have demonstrated that the augmentation of cholesterol generation is a hallmark of lipid metabolism during T cell activation and functions, by supporting the synthesis of cellular and organelle membrane ( 13 , 55 ). Retinoic acid receptor-related orphan receptors (RORs)-induced downregulation of cholesterol-metabolizing enzymes dramatically inhibits the proliferation and survival of CD8 + T cells ( 56 ). In addition, inhibition of acetyl‐CoA acetyltransferase (Acat) 1 and 2, enzymes involving in cholesterol esterification and storage, can further promote the proliferation and functions of CD8+ T cells by increasing cholesterol levels ( 57 ).…”

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model

“…Cholesterol maintains quiescence in naïve T cells and also paradoxically regulates exit from quiescence by modulating TCR nanocluster formation besides effecting signaling molecules (18)(19)(20). T cell activation induces an increase of intracellular cholesterol for proliferation, however self-regulation is secured by negative feedback pathways (21)(22)(23)(24). Moreover, cholesterol is also involved in the differentiation and stabilization of the different T cell subsets.…”