Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

Abstract

Regulatory T (T_reg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic T_reg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic T_reg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + T_reg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6C^highCCR2^highCx3Cr1^low monocytes and higher retention of proinflammatory Ly6C^midCCR2^highCx3Cr1^low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + T_reg compared with CVB3 + PBS mice. Coculture of T_reg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of T_reg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6C^lowCCR2^lowCx3Cr1^high subset. T_reg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + T_reg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + T_reg mice compared with CVB3 + PBS mice. In summary, adoptive T_reg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.