Platelet–NK cell interplay in advanced coronary artery disease is associated with pre-exhausted NK cell dysfunction without upregulation of the immune checkpoint receptor NKG2A

Platelet crosstalk with leukocytes plays a key role in the development of atherosclerosis. However, different immune cells are involved in the disease’s pathology, with Tregs showing protective effects against atherosclerosis, whereas NK cells appear to contribute to both atherogenic and atherothrombotic events. Given platelets’ potential to interact with immune cells, this study aims to investigate the role of NK cells in coronary artery disease (CAD) in relation to platelet activation. Samples from 30 CAD patients, candidates for CABG, and healthy individuals were subjected to flow cytometry analysis to evaluate platelet-derived microparticles (PMPs), P-selectin expression on platelets and PMPs, TGF-β1 expression associated with PMPs, platelet/PMP-NK cell conjugates, and major NK cell receptors. Soluble (s) TGF-β1 levels were measured by ELISA. Platelet P-selectin expression, Platelet microparticles (PMPs), their P-selectin/TGF-β1 expression, sTGF-β1, and platelet/PMPs-NK cell conjugates were significantly higher in CAD patients. NK cell levels, activating receptor expression, and cytotoxic potential were reduced in CAD and were inversely correlated with increased platelet P-selectin, sTGF-β1, and platelet/PMPs-NK cell conjugates. Increased levels of platelets/PMPs-associated or sTGF-β1 in CAD patients could act as major inhibitory signals, attenuating NK cell frequency and their functional competence. Intriguingly, this was consistent with a direct interaction between platelets/PMPs and NK cells, which showed an inverse correlation with the quantitative and qualitative characteristics of these cells. These findings, together with reduced expression of activating receptor and cytotoxic potential in the absence of checkpoint upregulation, suggest a pre-exhausted, dysfunctional NK-cell phenotype that may compromise innate immune competence. Whether this phenotype correlates with CAD severity or can be modulated by antiplatelet therapy warrants further investigation.