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

Figure 1. Pathogenesis of CAV: (a) Cellular immunity. Recipient NK cells recognize graft MHC-I and release TNF-α and IFN-γ, promoting endothelial inflammation. Activated dendritic cells and macrophages recruit T lymphocytes and produce cytokines such as IL-6, IL-17, etc. Allograft-infiltrating macrophages undergo metabolic reprogramming through the MEK1/2-PKM2 pathway, increasing TGF-β1 and sustaining inflammation. (b) Humoral immunity. B lymphocytes generate donor-specific antibodies and panel reactive antibodies that bind to the graft endothelium, which activate the classical complement pathway from C1 complex assembly to membrane attack complex (MAC) formation. This induces endothelial cytotoxicity, thrombosis, and exposure of cryptic epitopes, perpetuating immune-mediated vascular injury. (c) VSMC phenotypic switching. Inflammatory mediators such as PDGFs from inflammatory endothelium induce vascular smooth muscle cells to switch from contractile to synthetic phenotypes. This process involves AXL, MMP-14/CD44, and CYP2C signaling, leading to VSMC migration, proliferation, and extracellular matrix deposition in the intima. (d) Tertiary lymphoid structures. Lymphatic endothelial cells…

Figure 2. Treg phenotype, heterogeneity, and immunosuppressive mechanisms in cardiac transplantation: (a) Treg origin and induction. Naïve CD4+ T cells (CD25-Foxp3-) differentiate into thymus-derived natural Tregs (tTregs) through high-affinity TCR recognition of MHC-self-peptide complexes presented by stromal cells, acquiring Foxp3 expression (Foxp3+) and elevated CD25 levels (CD25high), and alternatively differentiate into peripheral-induced adaptive Tregs (pTregs) in peripheral lymphoid organs. (b) Factors maintaining the Treg phenotype. Cytokine and microRNA cooperatively stabilize Treg phenotype. IL-2 activates the STAT5 pathway to sustain Foxp3 expression, while IL-35 binds gp130 to activate STAT1, creating a positive feedback loop that enhances both Foxp3 stability and IL-35 secretion. Additionally, IL-35 facilitates CCR5-mediated migration, suppresses the Treg-weakening AKT-mTOR pathway, and upregulates immune checkpoints including PD-1 and TIGIT. At the post-transcriptional level, miR-155 promotes functional integrity by inhibiting SOCS1, a negative regulator of STAT5. miR-146a regulates Treg function through the IFN-γ/STAT1 pathway. Ablation of miR-146a promotes Treg…

Figure 3. Regulatory mechanism of Treg-associated signaling pathways in CAV: (a) PD-1/PD-L1 pathway. Donor-derived PD-L1, expressed on cardiomyocytes and M2 macrophages, engages PD-1 on Tregs to sustain peripheral immune tolerance and restrict Teff activation. PARP-1 inhibition augments PD-1 expression, thereby improving Treg stability and promoting cardiac allograft tolerance. (b) IL-33 pathway. Released passively as an alarmin after graft injury, IL-33 binds the ST2L receptor to increase Treg proliferation and immunosuppressive efficacy. By shifting immune responses toward Th2-type responses while suppressing Th1-type pathways, IL-33 mitigates inflammatory damage and prolongs allograft survival. (c) IL-6 pathway. Dysregulation of IL-6 signaling directly undermines Treg inhibitory function and disturbs the equilibrium between Tregs and inflammatory responses. IL-6 drives Th17 differentiation via RORγt and activates NK cells, both of which exacerbate CAV by promoting vascular intimal hyperplasia and facilitate graft rejection. (d) CTLA-4 pathway. CTLA-4-Ig inhibits Teff activation by obstructing the B7:CD28 costimulatory signaling pathway, thereby creating a milieu conducive to Treg…