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Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions.

Tseng CT, Klimpel GR - J. Exp. Med. (2002)

Bottom Line: CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells.These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells.Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-gamma production by NK cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT
Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide. Little is known about how this virus is able to persist or whether this persistence might be because of its ability to alter the early innate immune response. The major HCV envelope protein E2 has been shown to bind to CD81. Thus, HCV binding to natural killer (NK) cells could result in the cross-linking of CD81. To explore this possibility, we investigated whether cross-linking CD81 on NK cells could alter NK cell function. CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells. In this study, we show that CD81 cross-linking via immobilized E2 or mAbs specific for CD81 inhibits not only non major histocompatibility complex-restricted cytotoxicity mediated by NK cells but also interferon (IFN)-gamma production by NK cells after exposure to interleukin (IL)-2, IL-12, IL-15, or CD16 cross-linking. These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells. Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-gamma production by NK cells.

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Related in: MedlinePlus

Cross-linking of CD81 significantly inhibits IL-12– or IL-15–mediated IFN-γ production by NK cells. Purified NK cells (105 cells per well) were cultured in microtiter plates that were precoated with control IgG1 5 μg/ml antibody, 5 μg/ml anti-CD81, 5 μg/ml anti-E2, or immobilized E2 (5 μg/ml anti-E2/1 μg/ml E2 complex). Each culture contained 200 μl of medium supplemented with either IL-12 (500 U/ml) or IL-15 (5 U/ml). Supernatants were collected after 18 h and assessed for IFN-γ levels by ELISA. The amounts of IFN-γ are presented as mean (pg/ml) ± SD of duplicate samples. Data are representative of three independent experiments using different donors.
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fig2: Cross-linking of CD81 significantly inhibits IL-12– or IL-15–mediated IFN-γ production by NK cells. Purified NK cells (105 cells per well) were cultured in microtiter plates that were precoated with control IgG1 5 μg/ml antibody, 5 μg/ml anti-CD81, 5 μg/ml anti-E2, or immobilized E2 (5 μg/ml anti-E2/1 μg/ml E2 complex). Each culture contained 200 μl of medium supplemented with either IL-12 (500 U/ml) or IL-15 (5 U/ml). Supernatants were collected after 18 h and assessed for IFN-γ levels by ELISA. The amounts of IFN-γ are presented as mean (pg/ml) ± SD of duplicate samples. Data are representative of three independent experiments using different donors.

Mentions: IL-12 and IL-15 are two cytokines believed to play a crucial role in skewing the T cell response to a Th1 cytokine profile via the stimulation of IFN-γ production by NK cells (21, 22). Thus, the effect of CD81 cross-linking on IL-12– versus IL-15–mediated activation of NK cells was also investigated. Results from a representative experiment are shown in Fig. 2 . Cross-linking of CD81 by either immobilized E2 or anti-CD81 resulted in a significant reduction in IFN-γ production by IL-12– or IL-15–activated NK cells.


Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions.

Tseng CT, Klimpel GR - J. Exp. Med. (2002)

Cross-linking of CD81 significantly inhibits IL-12– or IL-15–mediated IFN-γ production by NK cells. Purified NK cells (105 cells per well) were cultured in microtiter plates that were precoated with control IgG1 5 μg/ml antibody, 5 μg/ml anti-CD81, 5 μg/ml anti-E2, or immobilized E2 (5 μg/ml anti-E2/1 μg/ml E2 complex). Each culture contained 200 μl of medium supplemented with either IL-12 (500 U/ml) or IL-15 (5 U/ml). Supernatants were collected after 18 h and assessed for IFN-γ levels by ELISA. The amounts of IFN-γ are presented as mean (pg/ml) ± SD of duplicate samples. Data are representative of three independent experiments using different donors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196015&req=5

fig2: Cross-linking of CD81 significantly inhibits IL-12– or IL-15–mediated IFN-γ production by NK cells. Purified NK cells (105 cells per well) were cultured in microtiter plates that were precoated with control IgG1 5 μg/ml antibody, 5 μg/ml anti-CD81, 5 μg/ml anti-E2, or immobilized E2 (5 μg/ml anti-E2/1 μg/ml E2 complex). Each culture contained 200 μl of medium supplemented with either IL-12 (500 U/ml) or IL-15 (5 U/ml). Supernatants were collected after 18 h and assessed for IFN-γ levels by ELISA. The amounts of IFN-γ are presented as mean (pg/ml) ± SD of duplicate samples. Data are representative of three independent experiments using different donors.
Mentions: IL-12 and IL-15 are two cytokines believed to play a crucial role in skewing the T cell response to a Th1 cytokine profile via the stimulation of IFN-γ production by NK cells (21, 22). Thus, the effect of CD81 cross-linking on IL-12– versus IL-15–mediated activation of NK cells was also investigated. Results from a representative experiment are shown in Fig. 2 . Cross-linking of CD81 by either immobilized E2 or anti-CD81 resulted in a significant reduction in IFN-γ production by IL-12– or IL-15–activated NK cells.

Bottom Line: CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells.These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells.Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-gamma production by NK cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT
Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide. Little is known about how this virus is able to persist or whether this persistence might be because of its ability to alter the early innate immune response. The major HCV envelope protein E2 has been shown to bind to CD81. Thus, HCV binding to natural killer (NK) cells could result in the cross-linking of CD81. To explore this possibility, we investigated whether cross-linking CD81 on NK cells could alter NK cell function. CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells. In this study, we show that CD81 cross-linking via immobilized E2 or mAbs specific for CD81 inhibits not only non major histocompatibility complex-restricted cytotoxicity mediated by NK cells but also interferon (IFN)-gamma production by NK cells after exposure to interleukin (IL)-2, IL-12, IL-15, or CD16 cross-linking. These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells. Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-gamma production by NK cells.

Show MeSH
Related in: MedlinePlus