Infusion of Induced Regulatory T Cells Alleviates Atherosclerosis by Reducing Pathological Macrophage‐Like Vascular Smooth Muscle Cells

Atherosclerosis remains the primary driver of cardiovascular and cerebrovascular morbidity and mortality. A pivotal event in its pathogenesis is the phenotypic conversion of vascular smooth muscle cells (VSMCs), particularly the transition from a contractile to a macrophage-like state. Using a murine model of atherosclerosis, we demonstrate that this process is orchestrated by a progressively disrupted perivascular immune milieu characterized by an expansion of CD44⁺ memory CD4⁺ T cells at the expense of CD44^- naive CD4⁺ T cells. Within this niche, CD44⁺ natural regulatory T cells (nTregs) actively promote VSMCs macrophage-like reprogramming, whereas their CD44^- counterparts exert an opposing, protective effect. Reciprocally, macrophage-like VSMCs foster the trans-differentiation of nTregs into pathogenic Th17 cells, amplifying vascular inflammation. In contrast, induced Treg cells (iTregs) display phenotypic stability and potently inhibit VSMCs macrophage-like switching, restrict pathological VSMCs migration, and curtail VSMCs survival. Systemic infusion of iTregs selectively remodels the perivascular immune microenvironment toward an antiatherogenic profile. Adoptive transfer of iTregs at early disease stages decreased the abundance of macrophage-like VSMCs, attenuated plaque burden, and these benefits were partially mediated by transforming growth factor β signaling. Collectively, iTreg-based cellular therapy represents a promising strategy to intercept VSMCs macrophage-like transformation and limit atherosclerotic progression.