Regulatory T cells in cardiac allograft vasculopathy: from mechanistic insights to clinical tolerance

Abstract

Cardiac allograft vasculopathy (CAV) is the primary impairment that influences the long-term prognosis of transplanted hearts. CAV is characterized by diffuse intimal hyperplasia of the coronary arteries, which is mediated by chronic inflammation, the alloimmune response, and vascular remodeling. Current immunosuppressive regimens effectively control acute rejection but have limited efficacy in preventing CAV and are associated with significant adverse effects upon long-term use. Regulatory T cells (Tregs) are essential for preserving immunological homeostasis and facilitating transplantation tolerance. They are pivotal in suppressing the activation of effector T cells (Teffs), modulating local inflammation, and postponing the progression of CAV. This review comprehensively elucidates the pathophysiology of and diagnostic advancements in CAV, emphasizes the phenotypic heterogeneity, immunosuppressive mechanisms, and protective role of Tregs in heart transplantation, and thoroughly discuss the interplay of PD-1/PD-L1, IL-33, IL-6, CTLA-4, fatty acid oxidation (FAO), and other signaling pathways in modulating Treg function and CAV pathogenesis. In terms of the translational medicine, the adoptive infusion of in vitro-expanded autologous Tregs has demonstrated the ability to postpone CAV in preclinical models; nonetheless, its clinical use is limited by cell stability, challenging preparation processes, and the lack of efficacy biomarkers. Therefore, this review seeks to establish a theoretical foundation and research viewpoint to comprehensively understand the immunological mechanisms of CAV and the advancement of novel Treg-targeted therapies.