Adoptive Transfer of Regulatory T Cells Protects Against Coxsackievirus-Induced Myocarditis

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Coxsackievirus (CVB) infection is a significant cause of myocarditis and dilated cardiomyopathy (DCM). The virus imparts autoimmunity through antigenic mimicry, cryptic epitopes, and adjuvant effect. Therefore an approach designed to reduce the immunopathological effects without impairing the development of anti-viral immunity would be beneficial in treating this or other infection-associated autoimmune disorders. Regulatory T cells (Tregs), play an important role in the negative regulation of immune responses. In this study, we attempted to test protective effect by adoptively transferring naturally occurring Tregs isolated from spleen to mice prior to infection with CVB3. CFSE-labeled CD4+CD25+Tregs of splenocytes were adoptively i.v. injected once every two weeks for 3 times to mice starting age of 5 weeks. The mice were then i.p. challenged with CVB3 immediately after the last cell transfer. Control groups were injected with CD4+T cells or PBS only. Adoptive transfer of Tregs significantly reduced mortality of infected mice compared to CD4+T cells injection group (P=0.0136) and PBS injection group (P=0.0589). Tregs also significantly decreased virus titer and inflammatory scores in the heart. Tregs were not only detected in the recipient spleen but also present n the infected heart. Both plasma cytokine levels and local inflammation in the heart and pancreas were suppressed in Treg group. Splenocytes proliferated equally in Tregs, CD4+T cell, and PBS group when stimulated with heat-inactivated virus; whereas, Tregs significantly reduced proliferation rate (P<0.05 vs CD4+T cell and PBS groups) when stimulated with heart homogenate, suggesting Tregs increased threshold of immune response which could tolerate self antigen. Tregs transfer also upregulated the TGFβ expression in the heart and prosurvival gene expression of phospho-AKT (p-AKT) compared to control groups. Although expression of LCK and ERK1/2 in the heart was not apparently changed, Coxsackievirus-adenovirus receptor (C AR) was decreased in the Tregs group. Pancreas as the virus reservoir also showed moderately reduced virus titer and inflammation in Tregs group. Conclusions: Adoptive transfer of Tregs protected against CVB3-induced myocarditis by suppressing immune response to the heart tissue and reduced CAR expression and virus titers probably by decreasing the inflammatory milieu favorite for virus replication and through increased expression of p-AKT to promote survival.