CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice

Regulatory T cells (Tregs), which are characterized by expression of CD4, CD25, and Foxp3, play a crucial role in the control of immune responses to both self and non-self Ags. To date, there are only limited data on their role in physiological and pathological hepatic immune responses. In this study, we examined the role of hepatic Tregs in immune-mediated liver injury by using the murine Con A-induced hepatitis model. Con A treatment was associated with an increased number of Foxp3(+) Tregs in liver but not in spleen. Moreover, the expression levels of Foxp3, CTLA-4, glucocorticoid-induced TNF receptor, as well as the frequency of CD103 of Tregs were increased after Con A injection, being significantly higher in liver than in spleen. Depleting CD25(+) cells aggravated liver injury, whereas adoptively transferring CD25(+) cells or Tregs reduced liver injury in Con A-treated recipients. Con A treatment induced elevated serum levels and hepatic mononuclear mRNA expressions of TGF-beta, which were reduced by Tregs depletion. In addition, anti-TGF-beta mAbs blocked the suppressive function of Tregs from Con A-treated mice in vitro. Finally, TGF-beta receptor II dominant-negative mice, whose T cells express a dominant negative form of TGFbetaRII and therefore cannot respond to TGF-beta, had a higher mortality rate and severer liver injury than normal mice injected with the same dose of Con A. These results indicate that CD4(+)CD25(+) Tregs play an important role in limiting the liver injury in Con A-induced hepatitis via a TGF-beta-dependent mechanism.