Abstract
Regulatory T cells (Tregs), which characteristically express forkhead box protein 3 (Foxp3), are essential for the induction of immune tolerance. Here, we investigated microRNA-146a (miR-146a), a miRNA that is widely expressed in Tregs and closely related to their homeostasis and function, with the aim of enhancing the function of Tregs by regulating miR-146a and then suppressing transplant rejection. The effect of the absence of miR-146a on Treg function in the presence or absence of rapamycin was detected in both a mouse heart transplantation model and cell co-cultures in vitro. The absence of miR-146a exerted a mild tissue-protective effect by transiently prolonging allograft survival and reducing the infiltration of CD4+ and CD8+ T cells into the allografts. Meanwhile, the absence of miR-146a increased Treg expansion but impaired the ability of Tregs to restrict T helper cell type 1 (Th1) responses. A miR-146a deficiency combined with interferon (IFN)-γ blockade repaired the impaired Treg function, further prolonged allograft survival, and alleviated rejection. Importantly, miR-146a regulated Tregs mainly through the IFN-γ/signal transducer and activator of transcription (STAT) 1 pathway, which is implicated in Treg function to inhibit Th1 responses. Our data suggest miR-146a controls a specific aspect of Treg function, and modulation of miR-146a may enhance Treg efficacy in alleviating heart transplant rejection in mice.
Highlights
Organ transplantation is an effective treatment for patients with end-stage organ failure, but immune rejection after transplantation is still one of the main factors affecting the survival rate and quality of life of patients [1,2,3]
Regulatory T cells (Tregs), which are characterized by the expression of the transcription factor forkhead box protein 3 (Foxp3), are a special population with immunoregulatory functions that inhibits the excessive activation of self-antigens, monitors the expansion of lymphocytes, and effectively suppresses excessive immune responses [6,7,8]
Γ/STAT1 pathway during rejection in mouse heart transplantation recipients, which is closely related to the ability of Tregs to suppress Th1 responses
Summary
Organ transplantation is an effective treatment for patients with end-stage organ failure, but immune rejection after transplantation is still one of the main factors affecting the survival rate and quality of life of patients [1,2,3]. Increasing the number of Tregs or strengthening their immunoregulatory function may ameliorate rejection and induce immune tolerance. While a sufficient number of Tregs is induced in vitro at the early stage of clinical transplantation, several factors, such as low purity, insufficient function, and variable phenotype, limit the infusion of Tregs, and the adoptive transfer of Tregs alone is not sufficient to induce immune tolerance, suggesting that a different therapeutic approach is required to overcome these shortcomings [11,12,13,14]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call