Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells

Coxsackievirus group B type 3 (CVB3) is a common etiologic agent of viral myocarditis and often causes sexually dimorphic myocarditis with increased incidence and mortality in male. So far, the underlying mechanism for the high male prevalence is not well elucidated. In this study, we deciphered the role of myeloid-derived suppressor cells (MDSCs) in the gender bias in murine CVB3-induced myocarditis by comparing their frequencies, subsets as well as immune suppressive functions. We found that much more myocardial MDSCs were enriched in infected females than males, with dramatically higher percentage ratio of CD11b(+)Ly6G-Ly6C(high) monocytic subset (M-MDSCs) to CD11b(+)Ly6G(+)Ly6C(low) granulocytic subset (G-MDSCs). Interestingly, more potent suppression on T cell proliferation was also evidenced in female-derived M-MDSCs. Consistently, adoptive transfer of female- but not male-derived M-MDSCs efficiently alleviated CVB3-induced myocarditis in male recipient mice, and this protection could be ascribed to the increased induction of regulatory and CD4(+)IL-10(+) T cells. Our study suggested that myocardial MDSCs were distinctively induced not only in quantities but also in phenotypes and immune suppressive functions in CVB3-infected males and females; and female-derived more suppressive M-MDSCs contributed to their insensitivity to CVB3-induced myocarditis.