Inhibition of Natural Killer Cells through Engagement of CD81 by the Major Hepatitis C Virus Envelope Protein

Abstract

The immune response against hepatitis C virus (HCV) is rarely effective at clearing the virus, resulting in ∼170 million chronic HCV infections worldwide. Here we report that ligation of an HCV receptor (CD81) inhibits natural killer (NK) cells. Cross-linking of CD81 by the major envelope protein of HCV (HCV-E2) or anti-CD81 antibodies blocks NK cell activation, cytokine production, cytotoxic granule release, and proliferation. This inhibitory effect was observed using both activated and resting NK cells. Conversely, on NK-like T cell clones, including those expressing NK cell inhibitory receptors, CD81 ligation delivered a costimulatory signal. Engagement of CD81 on NK cells blocks tyrosine phosphorylation through a mechanism which is distinct from the negative signaling pathways associated with NK cell inhibitory receptors for major histocompatibility complex class I. These results implicate HCV-E2–mediated inhibition of NK cells as an efficient HCV evasion strategy targeting the early antiviral activities of NK cells and allowing the virus to establish itself as a chronic infection.

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…During HCV infection, a possible disease-related mechanism leading to virus-mediated inhibition of NK cells could be represented by the specific interaction between viral E2 protein and CD81 molecules expressed on NK cells [33]. We therefore studied whether CD81 expression on freshly drawn purified NK cells is comparable in healthy donors and chronically HCV-infected viremic patients.…”

“…Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33]. In addition, reduced NK cell triggering mediated by reduced expression of NKG2D ligands (MIC-A and MIC-B) on mature DC (mDC) [34] as well as increased NK cell inhibition through increased CD94/NKG2A expression and TGF-b and IL-10 production [35,36,37] have been suggested to occur during HCV infection.…”

“…In addition, in the present work, cytokine production could be studied following stimulation by FO1 cells in only a limited number of patients. Additional studies for the characterization of cytokine production by NK cells in the presence of other cells including HepG2, K562 and DC are needed to improve our understanding of the mechanisms that may lead to failure of NK cell function during HCV infection with cells that may bear variable HLA-E molecule densities and to verify whether this is a mechanism shared by all chronically infected patients or is rather restricted to a subset of patients with different disease courses.The finding of increased NCR molecule expression in chronically HCV-infected patients in the absence of significant activation (as determined by HLA-DR surface expression) led us to study whether this could be related to mechanism(s) that prevent NK cell activation, such as CD81 crosslinking [33]. Although previous work has shown that CD16-mediated NK cell function can be inhibited by CD81 crosslinking [33], we found that NCRmediated cytotoxicity is not affected by CD81 crosslinking and that CD56 high CD16 low NK cells have a significantly decreased density of CD81.…”

MICA and recovery from hepatitis C virus and hepatitis B virus infections

“…10 There is evidence that natural killer (NK) cells contribute to HCV recovery, 11 and conversely that, at least in vitro, HCV may persist by interfering with NK activation. 12,13 How HCV infection promotes or inhibits activation of NK cells, and why there are person-to-person differences in the immune response are poorly understood.…”

Mission poorly accomplished: The protective role of natural killer cells in recurrent hepatitis C after liver transplantation

“…However, there is strong evidence in non-OLT patients with HCV to suggest that NK and NKT cells are involved in HCV clearance and in liver injury. [15][16][17] In the current issue of Liver Transplantation, Rosen and colleagues 18 provide a first insight into the significance and function of NK and NKT cells as a first line of defense against viral infections and liver injury caused by recurrent HCV after OLT. They used traditional flow cytometric analysis of cell surface antigens to identify NK (CD3-negative/CD56-positive) and NKT (CD3-positive/CD56-positive) cells in peripheral blood of patients with end-stage liver disease (HCV-infected and non-HCV-infected as controls) prior to OLT and provided functional characterization and correlation to post-OLT outcome.…”