Ribavirin modulates the conversion of human CD4(+)  CD25(-) T cell to CD4(+)  CD25(+)  FOXP3(+) T cell via suppressing interleukin-10-producing regulatory T cell

Because regulatory T (Treg) cells play an important role in modulating the immune system response against both endogenous and exogenous antigens, their control is critical to establish immunotherapy against autoimmune disorders, chronic viral infections and tumours. Ribavirin (RBV), an antiviral reagent used with interferon, is known to polarize the T helper (Th) 1/2 cell balance toward Th1 cells. Although the immunoregulatory mechanisms of RBV are not fully understood, it has been expected that RBV would affect T reg cells to modulate the Th1/2 cell balance. To confirm this hypothesis, we investigated whether RBV modulates the inhibitory activity of human peripheral CD4(+)  CD25(+)  CD127(-) T cells in vitro. CD4(+)  CD25(+)  CD127(-) T cells pre-incubated with RBV lose their ability to inhibit the proliferation of CD4(+)  CD25(-) T cells. Expression of Forkhead box P3 (FOXP3) in CD4(+)  CD25(-) T cells was down-modulated when they were incubated with CD4(+)  CD25(+)  CD127(-) T cells pre-incubated with RBV without down-modulating CD45RO on their surface. In addition, transwell assays and cytokine-neutralizing assays revealed that this effect depended mainly on the inhibition of interleukin-10 (IL-10) produced from CD4(+)  CD25(+)  CD127(-) T cells. These results indicated that RBV might inhibit the conversion of CD4(+)  CD25(-)  FOXP3(-) naive T cells into CD4(+)  CD25(+)  FOXP3(+) adaptive Treg cells by down-modulating the IL-10-producing Treg 1 cells to prevent these effector T cells from entering anergy and to maintain Th1 cell activity. Taken together, our findings suggest that RBV would be useful for both elimination of long-term viral infections such as hepatitis C virus infection and for up-regulation of tumour-specific cellular immune responses to prevent carcinogenesis, especially hepatocellular carcinoma.