Interaction of CD99 and its ligands regulates immunoregulatory pathways in NK cells.

Natural killer (NK) cells play a key role in immune defense against tumors and viral infections through a balance of activating and inhibitory receptors. CD99 is a transmembrane glycoprotein involved in many biological processes; however, its role in NK cell receptor modulation remains incompletely understood. In this study, we investigated the effect of CD99 engagement on NK cells using a recombinant CD99 fusion protein upon stimulation with cytokine, interleukin (IL)-2. Peripheral blood mononuclear cells (PBMCs) and purified NK cells were analyzed to evaluate changes in several receptor expressions. Flow cytometric analysis demonstrated that the interaction between CD99 and its ligands modulates NK cell phenotypes, particularly through downregulation of natural cytotoxicity receptors (NCRs). Differential effects were observed between PBMCs and purified NK cell cultures, indicating the surrounding immune cell environment influences CD99-mediated immunomodulatory responses. Despite receptor modulation, no significant changes in cytokine production were observed in NK cells. These findings suggest that CD99 and its ligand interactions contribute to the regulation of NK cell activation states and receptor dynamics under activated conditions in a context-dependent manner.