A Critical Role for IL-21 Receptor Signaling in the Coxsackievirus B3-Induced Myocarditis

To determine whether IL-21 receptor signaling plays a significant role in promoting Tfh cell-mediated cardiac injury in viral myocarditis (VMC), we compared IL-21R-deficient mice for some parameters of VMC. Balb/c and IL-21R^−/− mice were infected with CVB3. Frequencies of splenic Tfh cells were determined by flow cytometric analysis, and productions of anti-adenine nucleotide translocator (ANT) autoantibodies were detected by enzyme-linked immunosorbent assay. To determine the effects of IL-21R signal on the proliferation of B cells, lymphocytes from spleens of the IL-21R^−/− and Balb/c mice infected by CVB3 were tagged with carboxyfluorescein succinimidyl ester (CFSE) and then were stimulated with lipopolysaccharides plus IL-21 or anti-IL-21 neutralizing antibody for 3 days. The proliferation of B cells was analyzed by flow cytometry. Anti-ANT antibodies in the supernatants were detected by ELISA. Results showed that IL-21R^−/− mice developed significantly less inflammation of the myocardium than Balb/c mice. Numbers of the Tfh cells and levels of anti-ANT antibody were decreased in IL-21R^−/− mice, indicating IL-21 signaling plays a role on the Tfh cell response. The percentage of CD19⁺CFSE⁺ B cells decreased in IL-21R^−/− mice compared to VMC mice. And anti-ANT antibodies were detected at lower levels in cultured supernatant from IL-21R^−/− mice than in those from VMC mice. These data suggest that IL-21R signal may contribute to anti-ANT antibody production and expansion of B cells in VMC mice.