Myocardial infarction (MI) is a global health problem with a serious economic burden, which has been considered the main cause of cardiovascular morbidity and mortality (1). It is an irreversible consequence of coronary artery ischemia. Patients are prone to heart failure after MI, which directly affects their quality of life and prognosis (2). Ventricular remodeling plays a pivotal role in the pathological process of ventricular dysfunction after infarction. It is clinically characterized by ventricular dilation, with other changes including collagen deposition, scar formation, fibrosis, and hypertrophy (3). A variety of drugs have been used to inhibit left ventricular remodeling, such as angiotensin-converting enzyme inhibitors and beta-blockers (4). However, current therapeutic strategies for preventing adverse clinical outcomes remain limited. Therefore, exploring the pathological mechanisms of post-MI ventricular remodeling and developing more effective prevention and treatment strategies are receiving increasing emphasis.

Regulatory T cells (Tregs) are a major type of immune cells involved in MI (5). In recent years, with the deepening of research in immunology and cardiology, the role of Tregs in ventricular remodeling has gradually garnered attention (6–8). Activation of the inflammatory immune system post-MI affects myocardial damage repair. Excessive inflammation results in an increased infarct size and aggravates cardiac remodeling (9). Tregs are a crucial type of lymphocytes that exhibit anti-inflammatory effects (10). They have immunomodulatory and recovery-promoting roles in atherosclerosis (11), acute coronary syndrome (ACS) (12), and chronic heart failure (13). The current review focuses on the role and mechanisms of Tregs in immune-mediated cardiac remodeling following MI, aiming to provide novel perspectives for the treatment and prognosis of MI.

Post-MI ventricular remodeling refers to changes in the morphology, size, and tissue structure of the ventricle following myocardial ischemia and hypoxia caused by acute occlusion of the coronary artery. It is a process in which the heart initiates a series of adaptive responses for self-repair and compensation. Long-term and sustained pathological remodeling contributes to heart failure (4). At the histological level, the pathological changes manifest as cardiomyocyte hypertrophy, apoptosis, myofibroblast proliferation, and interstitial fibrosis in the non-infarcted area, leading to the progressive alteration in left ventricular myofibrillar structure (3, 14). The macroscopic manifestations include thinning of the infarcted myocardium, left ventricular dilation, and compensatory myocardial hypertrophy in the infarct border zone. This leads to an increase in both left ventricular end-diastolic and end-systolic volumes over time. The left ventricle gradually transitions from a normal ellipsoidal shape to a spherical one, with abnormal regional wall motion and decreased left ventricular ejection fraction (LVEF) (15).

The mechanisms underlying ventricular remodeling involve several aspects, including metabolic alterations in cardiomyocytes under ischemic and hypoxic conditions, activation of the neuroendocrine system, and changes in the extracellular matrix (16). In the hypoxic environment caused by MI, normal aerobic oxidation in cardiomyocytes is inhibited, and anaerobic glycolysis serves as the main source of energy. Although this metabolic switch can provide energy in a short period of time, the amount of ATP produced is much less than that from aerobic oxidation. Additionally, the accumulation of metabolites such as lactate may lead to intracellular acidosis and impaired cell function (17). After MI, the body rapidly initiates the activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. These systems collectively promote the development of ventricular remodeling by regulating extracellular matrix deposition and promoting cardiomyocyte hypertrophy and interstitial fibrosis (18). Changes in collagen, fibronectin, and other components of the extracellular matrix lead to disruption of connections between cardiomyocytes and enlargement of the ventricular cavity. Meanwhile, the imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) further exacerbates ventricular remodeling (2, 16, 19).

Immune response plays a significant role in post-MI healing and remodeling (20). Hypoxia and nutrients deficiency result in the death of cardiomyocytes, thereby triggering inflammation (21). Immune cells participate in all stages of MI progression, where they can both exacerbate the death of cardiomyocytes and promote the regeneration of damaged myocardium. Additionally, they regulate the dynamic and complex inflammatory responses (20, 22). Monocytes and macrophages in the infarct area are activated and polarized at different times. They produce pro-inflammatory or anti-inflammatory cytokines, regulate cardiomyocyte proliferation and apoptosis, and influence cardiac remodeling (23). T lymphocytes and B lymphocytes are recruited to the infarct area to remove and repair damaged cells and tissues (24, 25). Understanding the role of Tregs, as key inflammatory suppressive lymphocytes, in post-MI ventricular remodeling is helpful to develop effective therapeutic targets (26).

Tregs are a subset of CD4⁺ T cells, accounting for 5%-10% of circulating CD4⁺ T cells. The features of Tregs include high expression of CD25 (IL-2 receptor alpha chain), high expression of transcription factor Foxp3, and low expression of CD127 (IL-7 receptor) (27). Foxp3 is the core molecule responsible for the function of Tregs, and its expression level directly determines the immunosuppressive capacity (28). Foxp3 deficiency leads to severe systemic inflammatory diseases (29). Tregs can be categorized into two types: natural Tregs derived from the thymus and induced Tregs generated from peripheral effector T cells ( Table 1 ). They play different immunoregulatory roles under various physiological and pathological conditions (30).

The immunomodulatory function of Tregs is primarily characterized by the suppression of over-activated immune response. Tregs exert immunosuppressive function on effector cells of innate and adaptive immunity, such as macrophages, neutrophils, dendritic cells (DCs), and T cells, through the utilization of multiple mechanisms (31). There are three main mechanisms by which Tregs exert their suppressive effects, including cell-to-cell interactions, cytokine release, and interference with target cell metabolism ( Figure 1 ).

Tregs communicate directly with effector T cells or other immune cells through intercellular contact mechanisms. The surface of Tregs exhibits high expression of co-inhibitory receptors, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and programmed death-ligand 1 (PD-L1) (32). CTLA-4 competitively binds to B7 molecules (CD80, CD86) on the surface of DCs, preventing the interaction between CD28 and B7, thereby delivering inhibitory signals and suppressing the activation and proliferation of T cells (33). The binding of CTLA-4 to B7 mediates the expression of indoleamine 2,3-dioxygenase by DCs, which degrades tryptophan essential for T cell proliferation (34, 35). LAG-3 binds to MHC class II molecules on the cell membrane of DCs and inhibits the maturation of DCs through cytoplasmic signaling. PD-L1 binds to programmed death receptor 1 (PD-1) on B cells, inhibiting their proliferation and activation, and inducing B cell apoptosis (36).

Tregs release a variety of inhibitory cytokines, including interleukin (IL)-10, transforming growth factor-β (TGF-β), and IL-35, to regulate the immune response of target cells (37). IL-10 inhibits the secretion of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and IL-1β, by monocytes and macrophages (38). It also induces the transformation of pro-inflammatory M1 macrophages into anti-inflammatory and pro-repair M2 macrophages (39). Anti-IL-10 neutralizing antibodies block the inhibition of effector T cells mediated by Tregs (40). Intracellular TGF-β induces an increase in Foxp3 expression, promoting the generation of Tregs (41). Blocking TGF-β signaling reduces Tregs-mediated immunosuppression and exerts anti-tumor therapeutic effects (42). Similar to TGF-β and IL-10, IL-35 plays an important role in immunomodulation and immune homeostasis by regulating the development of Tregs (43).

Tregs exert their suppressive function by interfering with the metabolic pathways of target cells. Specifically, Tregs are able to deliver a large amount of cyclic adenosine monophosphate (cAMP) to effector T cells, interfering with their glycolysis and oxidative phosphorylation processes, thereby reducing the energy supply and proliferative capacity of effector T cells (44). Furthermore, Tregs compete with effector T cells to consume IL-2, which is a crucial cytokine necessary for the proliferation and survival of effector T cells. By limiting the availability of IL-2, Tregs induce effector T cell death and immunosuppression (45, 46). Tregs express the exonucleases CD39 and CD73 on their surface, which catalyze the production of adenosine from ATP. The adenosine activates adenosine receptor A2 on effector T cells, exerting an inhibitory effect (37). In addition, Tregs can inhibit effector T cell-mediated tumor clearance through cytolysis. Tregs induce apoptosis in effector T cells by producing granzyme and perforin, thereby reducing the number of effector cells and mediating immune suppression (47).

Tang et al. amplified Tregs in MI rats by using adoptive transfer and CD28 superagonist antibody. They confirmed that increasing Tregs number in infarcted hearts prevented adverse ventricular remodeling and improved cardiac function (48). This study demonstrates for the first time that Tregs have an important regulatory role in post-MI remodeling. Lin et al. provided evidence that the level of Tregs in peripheral blood is significantly reduced in patients with ACS, compared to those with stable angina pectoris and individuals with normal coronary arteries (49). The migration of circulating Tregs to the site of cardiac inflammation leads to a decrease in the number of peripheral Tregs and an increase in the peri-infarct area. Furthermore, the frequency of Tregs is positively correlated with LVEF in ACS patients. Prospective studies on the relationship between Tregs and cardiovascular risk showed that low level of circulating Tregs were associated with a higher risk of MI (50).

A recent study showed that the number of circulating Tregs in patients with acute MI (AMI) at 72h was higher than that in healthy controls and patients with cardiovascular risks such as type 2 diabetes, dyslipidemia, and smoking. And the IL-10 secreted by Tregs was increased in AMI (7). The reason for this phenomenon may be that Tregs counteracted the inflammatory response following acute ischemia. Further analysis revealed that the percentage of Tregs in AMI patients remained relatively unchanged at 3 months but significantly decreased after 6 months. At the 3-month point after AMI, patients with LVEF greater than 50% have higher levels of Tregs. These studies suggest that the cardiac function seems to be influenced by the number of Tregs. Tregs may play a pivotal role as a potential therapeutic target in the progression and prognosis of MI.

Although there is plenty of evidence supporting the benefits of Tregs in animal models of MI, it often takes a long time to translate these benefits into practical clinical applications for patients. Conventional tools for Tregs amplification include antibodies such as anti-CD3/CD28, and cytokines such as IL-2. As early as 2006, research institutions attempted to develop immunotherapies that activate endogenous Tregs. They conducted a Phase 1 trial using Tregs agonists in six healthy young volunteers (70). Within 90 minutes after receiving intravenous injection of the super-agonist anti-CD28 monoclonal antibody (TGN1412), all subjects experienced systemic inflammatory reactions, including headache, myalgia, nausea, diarrhea, and hypotension. Twelve hours later, patients were in critical condition and received cardiopulmonary support in the intensive care unit. Although all six subjects ultimately survived, this case nevertheless reveals the complexity and high risk of Tregs-activated therapy. A study conducted by Tian et al. evaluated the safety and efficacy of low-dose IL-2 in patients with ischemic heart disease (71). They demonstrated that low-dose subcutaneous injections of IL-2 successfully elevated Tregs levels without significant adverse effects. This indicates that low-dose IL-2 may have potential to treat ischemic heart disease. In addition to the activation of endogenous Tregs, the adoptive transfer of exogenous Tregs has also shown significant promise in improving post-MI ventricular remodeling (46, 48). It can be divided into autologous Tregs reinfusion and allogeneic Tregs transplantation. Autologous Tregs reinfusion has a lower risk of immune rejection. However, its preparation process is time-consuming and is influenced by the quantity and functionality of the patient’s own Tregs, which limits its application in AMI. In contrast, off-the-shelf allogeneic Tregs derived from healthy donors can be prepared and stored in advance, making them suitable for rapid treatment. Nevertheless, allogeneic Tregs may trigger host immune rejection, and their long-term survival and functional stability still require further optimization (26). Therefore, autologous Tregs may be more suitable for the regulation of chronic inflammation, while allogeneic Tregs may be more appropriate for rapid intervention during the acute phase of MI. In the future, large-scale studies will be needed to confirm its safety and efficacy.

Tregs play a crucial role in maintaining immune homeostasis through their antigen specificity. Antigen-specific Tregs suppress immune responses against specific antigens, demonstrating significant therapeutic potential in autoimmune diseases and transplant tolerance (72). However, the pathological process of MI involves multiple antigens and extensive inflammatory responses. Polyclonal Tregs possess a broader antigen recognition capability, enabling them to suppress multiple immune responses simultaneously, which may confer an advantage in the treatment of MI. Nonetheless, their non-specific suppression may increase the risk of infections or tumorigenesis. Thus, careful consideration of the balance between efficacy and safety remains essential for their clinical application.

In recent years, the clinical application of chimeric antigen receptor T (CAR-T) cell therapy is rapidly developing. CAR is a modified receptor that directs T cells to recognize and eliminate cells expressing the target antigen. Excessive myocardial fibrosis is known to be a cause of adverse ventricular remodeling after AMI. CD5-targeted lipid nanoparticles encapsulating modified mRNA can transiently generate CAR-T cells targeting fibroblast activation protein, reduce myocardial fibrosis and improve cardiac systolic and diastolic function in mouse models of heart failure (73). Targeted regulation of fibroblast activation protein provides new research insights for CAR-Treg cells to improve ventricular remodeling after MI.

Heart transplantation is an effective treatment for patients with end-stage heart failure, but it is limited by allograft rejection. Increasing the number of Tregs or enhancing their suppressive function can help prevent allograft rejection. In a mouse model of allogeneic heart transplant rejection, low-dose IL-2 increased Tregs infiltration in the spleen and graft, prolonged graft survival, and prevented chronic rejection (74). Studies have shown that the combination of matrine and tacrolimus can alleviate acute rejection in mouse allogeneic heart transplantation by inhibiting the maturation of DCs and increasing the proportion of Tregs, thereby mediating immune tolerance post-heart transplantation (75).

Adoptive transfer of exogenous Tregs or amplification of endogenous Tregs has demonstrated protective effects on post-MI ventricular remodeling. Extensive basic experimental research and rigorous evaluations of efficacy and safety are essential before conducting clinical studies. Future research should also address how to optimize the Tregs amplification pathway, how to maintain their stability, and how to direct them to target the infarct area, in order to successfully translate this new strategy into an effective clinical approach for the treatment of MI.

Increasing the function or number of Tregs can ameliorate post-MI ventricular remodeling, with the primary mechanisms encompassing the suppression of inflammatory response, reduction of cardiomyocyte apoptosis, modulation of cardiac fibroblast function, and promotion of angiogenesis ( Figure 2 ). Tregs are considered as potential therapeutic targets. In recent years, a growing number of studies have focused on facilitating the transition of Tregs from basic research to clinical applications. The development of biomimetic nanoparticles and engineered Tregs has also brought promises in this therapeutic field (76, 77). Future research needs to further delve into the role and mechanisms of Tregs after MI, and carry out necessary clinical trials. Effective utilization of Tregs may provide a new potential avenue for the treatment of MI.