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)