Abstract 18009: Treg is Recruited Into Myocardium Through Th17 Pathway as a Negative Feedback in Autoimmune Myocarditis
Background: Recent studies have described that autoimmune system is involved in cardiac inflammation. Previously, we reported that interleukin-17 (IL-17) producing helper T cells (TH17 cells) play essential roles in the induction of autoimmune myocarditis as an initiation process; however, the interrelationship of pro-inflammatory cells and regulatory cells remains to be addressed. In this study, we examined the pathophysiological significance of the interaction between TH17 cells and regulatory T (Treg) cells in cardiac inflammation using experimental autoimmune myocarditis (EAM) model.
Methods and Results: EAM was generated by injecting the myosin heavy chain peptides twice. Disease severity was increased up to 3 weeks after induction, and thereafter decreased. We focused on helper T cells and investigated the expression of T cell markers in the hearts, using quantitative RT-PCR. The expression of retinoic acid receptor-related orphan nuclear receptor (ROR) γt was up-regulated in the EAM hearts, accompanied by the up-regulation of Foxp3, master gene of regulatory T cell. In RORγt knock-out mice that are resistant to EAM, the enhanced expression of Foxp3 was not observed, suggesting that Treg cells infiltrate into inflamed myocardium concomitantly with TH17 cells. Importantly, neutralizing antibody against IL-17, one of the representative cytokines that TH17 cells produce, markedly decreased the expression of Foxp3 without suppressing the disease severity and the expression of RORγt, proposing that TH17 cells recruit Treg cells to inflamed region through Th17-related cytokine/chemokine systems at chronic phase of EAM. Indeed, EAM induced several kinds of chemokines, including RANTES, a chemokine that is reported to mobilize Treg cells, and IL-17 neutralizing antibody blocked the up-regulation of these chemokines. Finally, the blockade of Treg cell functions by anti-CD-25 antibody aggravated EAM, compared with control IgG, implying that the healing of cardiac inflammation is dependent on TH17-Treg pathway.
Conclusion: TH17 cells regulate EAM not only as an initiator of cardiac inflammation, but also a mediator of Treg-healing pathway. This is the first demonstration of the interaction between TH17 cells and Treg cells in myocarditis.
- © 2012 by American Heart Association, Inc.