tgf-β1 down-regulation of nkg2ddap10 and 2b4sap expression on human nk cells contributes to hbv persistencetgf-β1 nkg2ddap10和2 b4sap表达的下调对人类nk细胞导致乙肝病毒的持久性.pdf

TGF-b1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence 1 1,2 3 1 1,2 1,2 1,2 Cheng Sun , Binqing Fu , Yufeng Gao , Xiaofeng Liao , Rui Sun , Zhigang Tian *, Haiming Wei * 1 Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China, 2 Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China, 3 Department of Liver Diseases of the Second Affiliated Hospital of Anhui Medical University, Hefei, China Abstract The mechanism underlying persistent hepatitis B virus (HBV) infection remains unclear. We investigated the role of innate immune responses to persistent HBV infection in 154 HBV-infected patients and 95 healthy controls. The expression of NKG2D- and 2B4-activating receptors on NK cells was significantly decreased, and moreover, the expression of DAP10 and SAP, the intracellular adaptor proteins of NKG2D and 2B4 (respectively), were lower, which then impaired NK cell-mediated cytotoxic capacity and interferon-c production. Higher concentrations of transforming growth factor-beta 1 (TGF-b1) were found in sera from persistently infected HBV patients. TGF-b1 down-regulated the expression of NKG2D and 2B4 on NK cells in our in vitro study, leading to an impairment of their effector functions. Anti-TGF-b1 antibodies could restore the expression of NKG2D and 2B4 on NK cells in vitro. Furthermore, TGF-b1 induced cell-cycle arrest in NK cells by up-regulating the expression of p15 and p21 in NK cells from immunotolerant (IT) patients. We conclude that TGF-b1 may reduce the expre