Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with
cirrhosis or
hepatocellular carcinoma. The role of Tregs in the progression of
liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of
liver fibrosis. As a consequence of Tregs depletion, the expression of
matrix metalloproteinases (
MMPs) and tissue inhibitors of
metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with
fibrosis resolution. Kupffer cells (KCs) are the main source of
MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit
MMP expression of KCs even at a low ratio; and anti-
transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on
MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in
fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of
liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the
MMP/TIMP balance and that the suppression of KC-mediated
MMP expression contributed to the regulatory process.