Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function

Abstract

Regulatory T cells (Tregs) play a pivotal role in suppressing immune responses regulating behavior and gene expression in effector T cells, macrophages, and dendritic cells. Tregs infiltrate the infarcted myocardium; however, their role the inflammatory and reparative response after myocardial infarction remains poorly understood. We used FoxP3(EGFP) reporter mice to study Treg trafficking in the infarcted heart and examined the effects of Treg depletion on postinfarction remodeling using an anti-CD25 antibody. Moreover, we investigated the in vitro effects of Tregs on cardiac fibroblast phenotype and function. Low numbers of Tregs infiltrated the infarcted myocardium after 24-72 h of reperfusion. Treg depletion had no significant effects on cardiac dysfunction and scar size after reperfused myocardial infarction but accelerated ventricular dilation and accentuated apical remodeling. Enhanced myocardial dilation in Treg-depleted animals was associated with increased expression of chemokine (C-C motif) ligand 2 and accentuated macrophage infiltration. In vitro, Tregs modulated the cardiac fibroblast phenotype, reducing expression of α-smooth muscle actin, decreasing expression of matrix metalloproteinase-3, and attenuating contraction of fibroblast-populated collagen pads. Our findings suggest that endogenous Tregs have modest effects on the inflammatory and reparative response after myocardial infarction. However, the anti-inflammatory and matrix-preserving properties of Tregs may suggest a role for Treg-based cell therapy in the attenuation of adverse postinfarction remodeling.

Role of Lymphocytes in Myocardial Injury, Healing, and Remodeling After Myocardial Infarction

“…Recently, another study has also reported that depletion of Tregs enhances the number of macrophages in myocardium. 54 Monocytic cells sorted from Treg-depleted mice showed significantly higher expression of inducible nitric oxide synthase 5 days post-MI when compared with cells sorted from control mice. Moreover, the expression of M2-associated anti-inflammatory cytokines IL-10 and transforming growth factor β1 was downregulated.…”

Identification of altered pathways in hypertrophic cardiomyopathy based on combined data of protein-protein interactions and molecular pathways

“…Regulatory T cells are found in the cardiac tissue and play important roles in modulating immune responses (Saxena et al, 2014). Kuusisto et al (2012) demonstrated that CD3 + T cells were present in HCM patients, but were lacking in healthy subjects, suggesting that inflammation due to infiltrating immune cells is associated with HCM.…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…Platelets have been suggested to be an important source of TGF-β1 in the pressureoverloaded myocardium (29); however, their role as a source of growth factors in the infarcted myocardium has not been systematically investigated. Lymphocyte subsets and mast cells infiltrate the infarcted heart (30)(31)(32)(33) and are capable of producing TGF-βs. Moreover, much like most tissues, the normal myocardium may contain constitutive stores of matrix-bound latent TGF-β that can be activated following injury (34), initiating a response even in the absence of de novo synthesis.…”

“…TGF-β also serves as a central mediator in T lymphocyte differentiation and activation, critically regulating phenotype and function of all subpopulations (69)(70)(71). Although activated subsets of T lymphocytes have been implicated in repair and remodeling of the infarcted heart (30,32,72), the relative role of TGF-β signaling in their recruitment and activation has not been investigated.…”