TGF-β1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence

PLoS Pathogens, Mar 2012

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-γ production. Higher concentrations of transforming growth factor-beta 1 (TGF-β1) were found in sera from persistently infected HBV patients. TGF-β1 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-β1 antibodies could restore the expression of NKG2D and 2B4 on NK cells in vitro. Furthermore, TGF-β1 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-β1 may reduce the expression of NKG2D/DAP10 and 2B4/SAP, and those IT patients who are deficient in these double-activating signals have impaired NK cell function, which is correlated with persistent HBV infection.

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TGF-β1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence

et al. (2012) TGF-b1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence. PLoS Pathog 8(3): e1002594. doi:10.1371/journal.ppat.1002594 TGF-b1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence Cheng Sun 0 Binqing Fu 0 Yufeng Gao 0 Xiaofeng Liao 0 Rui Sun 0 Zhigang Tian 0 Haiming Wei 0 Christopher M. Walker, Nationwide Children's Hospital, United States of America 0 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 1 www.plospathogens.org 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 expression of NKG2D/DAP10 and 2B4/SAP, and those IT patients who are deficient in these double-activating signals have impaired NK cell function, which is correlated with persistent HBV infection. - Funding: This work was supported by the Ministry of Science & Technology of China (973 Basic Science Project 2012CB519004, 2009CB522403) and the Natural Science Foundation of China (#30730084, #31021061, #91029303, #30911120480). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Hepatitis B virus (HBV) infects more than 350 million people worldwide, accounting for over 1 million deaths annually due to immune-mediated chronic liver damage [13]. The course of HBV infection is complicated. Three phases of chronic HBV (CHB) infection are now widely accepted: 1) an immune tolerant (IT) phase, characterised by an HBV DNA concentration .200,000 IU/mL, normal alanine aminotransferase (ALT) levels, normal liver biopsy or only minimal inflammation and perinatal infection of infants born to HBsAg/HBeAg-positive mothers; 2) an immune active (IA) phase, which is also referred to as the chronic hepatitis B phase or the immune clearance phase, characterised by an HBV DNA concentration .20,000 IU/mL, elevated ALT levels and active hepatic inflammation on biopsy; and 3) an inactive (IN) phase, characterised by HBV DNA levels ,2000 IU/mL, normal ALT levels and minimal or absent hepatic inflammation [4]. During the IA phase, the immune system of the host recognises the virus as foreign and initiates the immune clearance response, which results in hepatocyte damage. After one or more episodes of reactivation to the IA phase, patients begin the IN phase [57]. Patients in the IT phase have normal ALT levels and elevated levels of HBV DNA, commonly well above 1 million IU/mL; this phase can last anywhere from a few to .30 years [8]. The IT phase has been suggested to occur most frequently in patients who were infected via perinatal transmission from HBeAg-positive mothers [9]. In China, approximately 2 million infants are infected with HBV via perinatal transmission from HBsAg/HBeAg-positive mothers annually, and many of them are at high risk of developing chronic liver inflammation resulting in cirrhosis and hepatocellular carcinoma (HCC) in later life [1013]. The risk of developing HCC with HBV infection is higher in East Asian countries than in Western countries, possibly due to the frequency of earlier viral infection [14]. During the IT phase of CHB infection, the virus evolves strategies to evade immune clearance in the majority of patients. However, the tolerance mechanism of the IT phase has not been widely studied. Due to their normal ALT levels, there is no available treatment to reduce the very high HBV DNA levels or alleviate psychological pressure in IT-phase patients. The development of an anti-HBV therapy for such patients will require insight into the mechanisms o (...truncated)


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Cheng Sun, Binqing Fu, Yufeng Gao, Xiaofeng Liao, Rui Sun, Zhigang Tian, Haiming Wei. TGF-β1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence, PLoS Pathogens, 2012, Volume 8, Issue 3, DOI: 10.1371/journal.ppat.1002594