Physically interacting immune cells in cardiometabolic disease: established platelet-immune aggregates and emerging leukocyte-leukocyte complexes

Abstract

Chronic immune activation contributes to cardiometabolic disease and has most often been attributed to soluble mediators or changes in individual immune-cell subsets. A complementary dimension of immune organization is captured by direct physical interactions between immune cells, detected in blood or dissociated samples. While most dual-lineage flow-cytometric events should still be excluded as technical doublets, a validated subset represents true cell-cell conjugates (i.e., physically interacting immune cells rather than antibody-antigen complexes). The evidence base, however, is uneven as platelet-leukocyte aggregates are well-established biomarkers of platelet activation and thromboinflammation, while circulating non-platelet immune cell-cell complexes, particularly T cell-monocyte complexes, remain an emerging field supported by relatively few primary studies. Across acute infection and vaccination, these complexes appear regulated and may reflect coordinated immune activation. In chronic inflammatory states, including HIV and metabolic dysfunction, persistent complexes have been associated with inflammation and cardiometabolic risk, although mechanistic and causal data remain limited. Here, we review the current evidence for circulating immune cell complexes, distinguish established platelet-containing aggregates from the nascent literature on other immune-cell pairings, discuss candidate mechanisms that may support their formation and persistence, outline methodological requirements for their study, and consider their potential as biomarkers and therapeutic-response tools in cardiometabolic disease.