CD69-OxLDL Ligand Engagement Induces Programmed Cell Death 1 (PD-1) Expression in T Lymphocytes

Abstract

The mechanisms that control the inflammatory-immune response play a key role in tissue remodeling in cardiovascular diseases. T cell activation receptor CD69 binds oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also PD-1. These results were confirmed using oxLDL and an agonistic monoclonal antibody against CD69. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 were increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Our results underscore a novel mechanism of induction of PD-1, independent of TCR, signaling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodeling in cardiovascular diseases.