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CD4⁺CD25⁺ Foxp3⁺ Regulatory T Cells Protect against T Cell-Mediated Fulminant Hepatitis in a TGF-β-Dependent Manner in Mice¹

Hua-Xing Wei^*, Ya-Hui Chuang, Bofeng Li^*, Haiming Wei^*, Rui Sun^*, Yuki Moritoki, M. Eric Gershwin, Zhe-Xiong Lian^2, and Zhigang Tian^2,*

^* Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China; and Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA 95616

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-β, which were reduced by Tregs depletion. In addition, anti-TGF-β mAbs blocked the suppressive function of Tregs from Con A-treated mice in vitro. Finally, TGF-β receptor II dominant-negative mice, whose T cells express a dominant negative form of TGFβRII and therefore cannot respond to TGF-β, 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-β-dependent mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding provided by Natural Science Foundation of China (30721002, 30730084, 30630059, 30671901, and 30570819), Ministry of Science & Technology of China (973 Basic Science Project 2007CB512405, 2007CB512807, 2006CB504300, and 2004CB518807), and National Institutes of Health grants (DK074768, DK39588, N01-DK-9-2310, and R21DK077961).

² Address correspondence and reprint requests to Dr. Zhigang Tian, School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, China. E-mail address: tzg{at}ustc.edu.cn; or Dr. Zhe-Xiong Lian, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 East Health Sciences Drive, 6605A, Davis, CA 95616. E-mail address: zxlian{at}ucdavis.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; GITR, glucocorticoid-induced tumor necrosis factor receptor; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; HCC, hepatocellular carcinoma; dnTGFβRII, TGF-β receptor II dominant-negative; bw, body weight; MNC, mononuclear cell; ALT, alanine aminotransferase; AST, asparate aminotransferase.