Highlights
- Discovery of a 2-phase Treg specialization process: Naive Tregs in mediastinal lymph nodes differentiate into tissue-resident, reparative Tregs in the heart.
- Identification of CCR8 as a definitive marker and functional driver for heart-accumulated Tregs with high immunosuppressive and tissue-repair signatures.
- Validation of the CCL1-CCR8 axis: Macrophage-derived CCL1 is essential for the recruitment of CCR8+ Tregs to the infarcted myocardium.
- Mechanistic insight into IL-1R2: Tregs facilitate the anti-inflammatory shift of cardiac macrophages by secreting interleukin 1 receptor type 2.
- Clinical relevance: Elevated levels of CCR8+ Tregs and CCL1 are confirmed in both circulating blood and cardiac tissues of patients with myocardial infarction.
Background
Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide, primarily due to the subsequent progression toward heart failure. The pathophysiology of post-MI injury is characterized by an initial burst of intense inflammation followed by a resolution phase critical for tissue repair and remodeling. A failure to transition from a pro-inflammatory to a pro-reparative environment leads to adverse ventricular remodeling and chronic cardiac dysfunction.
Regulatory T cells (Tregs), characterized by the expression of the transcription factor Foxp3, are central players in maintaining immune homeostasis. In the context of the heart, Tregs have been shown to accumulate post-MI to limit excessive inflammation and promote healing. However, the precise molecular cues that drive their recruitment and the pathways through which they adapt to the unique cardiac microenvironment have remained elusive. Historically, therapeutic strategies aimed at global immune suppression have largely failed in cardiovascular medicine, highlighting the need for more targeted approaches. Identifying the specific subset of Tregs responsible for cardiac protection and understanding their recruitment trajectory is essential for developing next-generation immunomodulatory therapies.
Key Content
Mapping the Developmental Trajectory of Heart-Specific Tregs
Using a combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing in murine models of MI, researchers have delineated a stepwise differentiation process. The journey begins in the mediastinal lymph nodes (mLN), where naive Tregs reside. Upon MI, these cells undergo a metabolic and phenotypic shift, eventually migrating to the heart.
Trajectory analysis revealed that heart-resident Tregs do not arrive in their final functional state. Instead, they progress through a transitional phase where they acquire specific receptors and effector molecules. A key discovery in this trajectory is the progressive acquisition of CCR8 (CC motif chemokine receptor 8). As Tregs transition from the mLN to the infarcted myocardium, CCR8 expression increases significantly, coinciding with an enhanced reparative capacity. These CCR8+ Tregs exhibit a distinct transcriptomic profile enriched for genes associated with immunosuppression (e.g., Il10, Ctla4) and tissue repair (e.g., Areg), distinguishing them from the general Treg population.
The Essential Role of CCR8 in Cardiac Protection
Functional validation using Treg-specific CCR8 knockout mice (Ccr8flox/floxFoxp3Cre) provided definitive evidence of the receptor’s importance. Mice lacking CCR8 specifically on Tregs exhibited significantly reduced Treg accumulation in the heart following MI. This reduction in the regulatory population led to a cascade of adverse effects:
- Worsened Cardiac Function: Echocardiographic assessments showed significantly lower ejection fractions and increased ventricular dilation in knockout mice compared to controls.
- Heightened Inflammation: Histological analysis revealed a higher density of CD8+ T cells and natural killer (NK) cells in the infarcted area, indicating a failure to suppress cytotoxic immune responses.
- Pro-inflammatory Macrophage Dominance: In the absence of CCR8+ Tregs, cardiac macrophages maintained a pro-inflammatory (M1-like) phenotype for longer periods, exacerbating tissue damage.
Deciphering the CCL1-CCR8 Recruitment Axis
Recruitment of immune cells to the heart is mediated by chemokine-receptor interactions. This study identified CCL1 (CC motif chemokine ligand 1) as the primary ligand for CCR8 in the infarcted heart. Interestingly, the source of CCL1 was pinpointed to cardiac macrophages.
Experimental manipulation of CCL1 levels confirmed its role. CCL1 knockout mice or those with macrophage-targeted CCL1 knockdown showed impaired Treg infiltration and aggravated ventricular remodeling. Conversely, the overexpression of CCL1 promoted Treg recruitment and improved cardiac outcomes. Crucially, the protective effects of CCL1 were completely abolished in DEREG mice (where Tregs can be depleted) and in Ccr8flox/floxFoxp3Cre mice, proving that the CCL1-mediated benefit is strictly dependent on the recruitment of CCR8+ Tregs. This establishes a feedback loop where macrophages recruit the very cells (Tregs) that eventually modulate their own phenotype.
Mechanistic Insight: IL-1R2 and Macrophage Polarization
Beyond recruitment, the study explored how CCR8+ Tregs exert their reparative influence. One major mechanism identified is the secretion of Interleukin 1 Receptor Type 2 (IL-1R2). IL-1R2 acts as a decoy receptor for IL-1β, one of the most potent pro-inflammatory cytokines in the post-MI heart. By secreting IL-1R2, CCR8+ Tregs sequester IL-1β, thereby preventing it from binding to its signaling receptor on macrophages. This inhibitory action facilitates the polarization of macrophages from a pro-inflammatory state toward an anti-inflammatory, pro-reparative phenotype, which is essential for stable scar formation and preservation of myocardial integrity.
Human Validation and Clinical Relevance
To ensure translational applicability, the researchers examined clinical samples. In patients who had recently suffered an MI, there was a significant increase in the frequency of circulating CCR8+ Tregs compared to healthy controls. Furthermore, analysis of cardiac tissue from MI patients confirmed the presence of CCL1-expressing macrophages and infiltrated CCR8+ Tregs. These findings suggest that the CCL1-CCR8 axis is not merely a murine phenomenon but a conserved human mechanism of cardiac immune regulation, making it a viable target for clinical intervention.
Expert Commentary
The identification of the CCL1-CCR8 axis represents a significant leap forward in cardio-immunology. For years, the scientific community has sought a “handle” to specifically target the reparative subset of Tregs without inducing systemic immunosuppression. The specificity of CCR8 to tissue-resident, highly active Tregs offers exactly that handle.
One of the most compelling aspects of this research is the elucidation of the crosstalk between macrophages and Tregs. The fact that macrophages essentially “call for help” by secreting CCL1 to recruit Tregs, which then return the favor by modulating the macrophage phenotype via IL-1R2, highlights the elegance of immune coordination in tissue repair.
However, moving toward clinical application requires caution. While CCL1 overexpression showed benefits in mice, the timing and dosage in humans must be meticulously refined. Over-stimulating the Treg response could theoretically lead to localized immunosuppression that might interfere with the necessary early clearance of necrotic debris. Nonetheless, the high expression of CCR8 on heart Tregs—and its relative rarity on other T cell subsets—makes it an attractive candidate for agonist therapies or cell-based therapies where Tregs are pre-conditioned to express high levels of CCR8 before re-infusion.
Conclusion
The study by Li et al. provides a comprehensive roadmap of Treg adaptation in the infarcted heart, establishing the CCR8+ subset as a critical protector of cardiac function. By mapping the trajectory from lymph nodes to the heart and identifying the CCL1-CCR8 axis as the primary recruitment engine, this research opens new avenues for therapeutic repair. Future studies should focus on whether pharmacological agonists of CCR8 or recombinant IL-1R2 can mimic these cardioprotective effects in large animal models, potentially leading to a new class of immunomodulatory treatments for myocardial infarction.
References
- Li N, Hao Z, Yang H, Cai J, Liu M, He J, Gao R, Shen Y, Chen Z, Lu Y, Tang T, Zhang M, Jiao J, Yang F, Li J, Gu M, Hu D, Wang W, Wang Q, Chen C, Shan Z, Xia N, Cheng X. CCR8 Expression on Regulatory T Cells Reveals Trajectories of Tissue Adaptation and Protects Against Myocardial Infarction-Induced Tissue Damage. Circulation. 2026 Feb 13. doi: 10.1161/CIRCULATIONAHA.125.076426. Epub ahead of print. PMID: 41685444.