Regulatory T cells ameliorate cardiac remodeling after myocardial infarction

Abstract

Persistent inflammatory responses participate in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We hypothesized that regulatory T (Treg) cells modulate inflammatory responses, attenuate ventricular remodeling and subsequently improve cardiac function after MI. Acute MI was induced by ligation of the left anterior descending coronary artery in rats. Infiltration of Foxp3(+) Treg cells was detected in the infarcted heart. Expansion of Treg cells in vivo by means of adoptive transfer as well as a CD28 superagonistic antibody (JJ316) resulted in an increased number of Foxp3(+) Treg cells in the infarcted heart. Subsequently, rats with MI showed improved cardiac function following Treg cells transfer or JJ316 injection. Interstitial fibrosis, myocardial matrix metalloproteinase-2 activity and cardiac apoptosis were attenuated in the rats that received Treg cells transfer. Infiltration of neutrophils, macrophages and lymphocytes as well as expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were also significantly decreased, and the CD8(+) cardiac-specific cytotoxic T lymphocyte response was inhibited. Expression of interleukin (IL)-10 in the heart, however, was increased. Additional studies in vitro indicated that Treg cells directly protect neonatal rat cardiomyocytes against LPS-induced apoptosis, and this protection depends on the cell-cell contact and IL-10 expression. Furthermore, Treg cells inhibited proinflammatory cytokines production by cardiomyocytes. These data demonstrate that Treg cells serve to protect against adverse ventricular remodeling and contribute to improve cardiac function after myocardial infarction via inhibition of inflammation and direct protection of cardiomyocytes.

Allogenicity of Human Cardiac Stem/Progenitor Cells Orchestrated by Programmed Death Ligand 1

“…Insufficient recruitment of Treg worsens ventricular remodeling, 33 whereas adoptive transfer of Treg in a rat model of MI prevents adverse cardiac remodeling at the infarcted site, reduces macrophage and T-cell infiltration to the site, and protects the resident cardiomyocytes against apoptosis. 34 Our results strongly suggest that the administration of allogeneic hCPC would, through activation and expansion of Treg, provide similar protective/reparative effects. The mechanisms by which stem cells promote cardiac repair are not yet fully understood.…”

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

“…Thereby, they attenuate proinflammatory cytokine expression and immune cell infiltration post MI. 52 Our results indicate strongly modulated innate immunity, especially the induction of an M2-like differentiation of heart-infiltrating monocytes as the basis for the protective effect of superagonist-mediated Treg stimulation after MI. 21 Anti-CD28 superagonistic antibodies differ from conventional CD28-specific antibodies by their ability to activate T-cells without TCR ligation.…”

“…Expanding Treg cells in vivo, by either adoptive transfer of Tregs or a CD28-superagonistic antibody, attenuates myocardial proinflammatory cytokine expression and immune cell infiltration post MI. 52 In vitro data also indicate that Tregs might directly protect against apoptosis. Accordingly, a single adoptive Treg transfer in a permanent MI mouse model attenuates both the postinfarction inflammatory response and adverse remodeling.…”

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

“…The fundamental importance of the regulatory T cells in preventing cell-mediated damage to tissues is known to be mediated through direct interaction with target cells and/or secretion of soluble factors, such as IL-10 and TGF-␣ (13,31,32,40). A model of genetic Treg-cell ablation (FOXP3-DTR-mice) established that the depletion of Treg-cell compartments before MI induction resulted in aggravated cardiac inflammation and deteriorated clinical outcome associated with a M1-like macrophage polarization.…”