Transcriptomic Analysis Reveals Receptor Subclass-Specific Immune Regulation of CD8⁺ T Cells by Opioids

Opioid peptides are released at sites of injury, and their cognate G protein-coupled opioid receptors (OR) are expressed on immune cells. Exposure of human circulating CD8⁺ T cells to selective OR agonists differentially regulates thousands of genes. Gene set enrichment analysis reveals that μ-OR more strongly regulates cellular processes than δ-OR. In TCR naive T cells, triggering μ-OR exhibits stimulatory and inhibitory patterns, yet when administered prior to TCR cross-linking, a μ-OR agonist inhibits activation. μ-OR, but not δ-OR, signaling is linked to upregulation of lipid, cholesterol, and steroid hormone biosynthesis, suggesting lipid regulation is a mechanism for immune suppression. Lipid rafts are cholesterol-rich, liquid-ordered membrane domains that function as a nexus for the initiation of signal transduction from surface receptors, including TCR and μ-OR. We therefore propose that μ-OR-specific inhibition of TCR responses in human CD8⁺ T cells may be mediated through alterations in lipid metabolism and membrane structure.