Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism

Abstract

Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-β1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.

The IL-2/Anti-IL-2 Complex Attenuates Cardiac Ischaemia-Reperfusion Injury Through Expansion of Regulatory T Cells

“…We first observed that activated Treg cells appear in response to MIRI, consistent with previous reports that Treg cells are detected in heart tissue with MIRI [32]. In addition, we observed a rapid infiltration of Tregs in heart draining lymph nodes, beginning at 3 days and peaking at 7 days post-reperfusion, suggesting specific recruitment of Tregs from the peripheral blood to the infarct, and from the heart to immune organs, which is driven by MIRI.…”

“…The majority of previous experimental studies on post-MI healing have demonstrated that Tregs play a protective role in this process [13, 19, 32, 45]. However, Mathes et al found that endogenous and MHC-II non-restricted Foxp3+ T-cells could drive MIRI [47].…”

“…Additional evidence suggests that Th17 cells and interleukin (IL)–17, which are related to autoimmune diseases, may play an important role in MIRI [4]. In contrast, other studies have demonstrated that CD4+CD25+Foxp3+ Tregs exert a protective effect against pathology [32]. …”

“…Previous studies in our laboratory demonstrated that the adoptive transfer of in vitro -activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect [32]. However, adoptive transfer therapy using Tregs is limited by inadequate purity of isolated Treg cell populations, insufficient numbers for transfer, and potential instability [33].…”

‘Repair’ Treg Cells in Tissue Injury

“…The role of CD39 on Tregs in limiting tissue injury has been studied in myocardial infarction (MI) [74]. Elevated levels of CD39 can be observed in Treg populations in MI patients after primary percutaneous coronary intervention (PCI).…”