TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence

PLoS Pathog. 2012;8(3):e1002594. doi: 10.1371/journal.ppat.1002594. Epub 2012 Mar 15.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD / metabolism*
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Viral
  • Hepatitis B virus / immunology
  • Hepatitis B, Chronic / immunology
  • Hepatitis B, Chronic / metabolism*
  • Hepatitis B, Chronic / virology
  • Humans
  • Immunity, Innate / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Male
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Receptors, Immunologic / metabolism*
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Transforming Growth Factor beta1 / genetics*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antigens, CD
  • CD244 protein, human
  • HCST protein, human
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • SH2D1A protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • TGFB1 protein, human
  • Transforming Growth Factor beta1