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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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CD81 cross-linking inhibits the cytotoxic activities of fresh NK cells. The standard 4-h chromium release assay was used to assess NK cell–mediated cytotoxicity. Varying numbers of freshly isolated NK cells were cultured in microtiter wells precoated control IgG1, anti-CD81, or anti-CD56 antibody at 1 μg/ml of each antibody, 5 μg/ml anti-E2, or immobilized E2 (1 μg/ml anti-E2/E2) for 30 min before addition of 51Cr-labeled K-562 (104 cells per well). Effector:target cell ratios of 20, 10, 5, and 2.5 were used in each experiment. Spontaneous releases for K-562 were always below 10%. Specific lysis is presented as mean percentage ± SD of duplicate samples. Data are representative of six independent experiments using different cell preparations.
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fig5: CD81 cross-linking inhibits the cytotoxic activities of fresh NK cells. The standard 4-h chromium release assay was used to assess NK cell–mediated cytotoxicity. Varying numbers of freshly isolated NK cells were cultured in microtiter wells precoated control IgG1, anti-CD81, or anti-CD56 antibody at 1 μg/ml of each antibody, 5 μg/ml anti-E2, or immobilized E2 (1 μg/ml anti-E2/E2) for 30 min before addition of 51Cr-labeled K-562 (104 cells per well). Effector:target cell ratios of 20, 10, 5, and 2.5 were used in each experiment. Spontaneous releases for K-562 were always below 10%. Specific lysis is presented as mean percentage ± SD of duplicate samples. Data are representative of six independent experiments using different cell preparations.

Mentions: To determine whether cross-linking of CD81 can modulate NK cell–mediated cytotoxicity, freshly isolated and purified NK cells were incubated for 30 min in microtiter wells precoated with one of the following: (i) isotype matched control IgG1; (ii) anti-CD81; (iii) anti-CD56; (iv) anti-E2; or (v) immobilized E2. Non-MHC–restricted cytotoxic activity was then assessed against K562 tumor cells. A representative experiment is presented in Fig. 5 . No alteration in NK cell cytotoxic activity was observed when CD56 was cross-linked on NK cells or when NK cells were exposed to immobilized control IgG1 or mAb to E2. However, the cross-linking of CD81 on NK cells via either immobilized E2 or anti-CD81 resulted in a significant reduction in the cytolytic activity. Identical results were also observed when assessing IL-2–activated NK cells (data not presented).


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

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

CD81 cross-linking inhibits the cytotoxic activities of fresh NK cells. The standard 4-h chromium release assay was used to assess NK cell–mediated cytotoxicity. Varying numbers of freshly isolated NK cells were cultured in microtiter wells precoated control IgG1, anti-CD81, or anti-CD56 antibody at 1 μg/ml of each antibody, 5 μg/ml anti-E2, or immobilized E2 (1 μg/ml anti-E2/E2) for 30 min before addition of 51Cr-labeled K-562 (104 cells per well). Effector:target cell ratios of 20, 10, 5, and 2.5 were used in each experiment. Spontaneous releases for K-562 were always below 10%. Specific lysis is presented as mean percentage ± SD of duplicate samples. Data are representative of six independent experiments using different cell preparations.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: CD81 cross-linking inhibits the cytotoxic activities of fresh NK cells. The standard 4-h chromium release assay was used to assess NK cell–mediated cytotoxicity. Varying numbers of freshly isolated NK cells were cultured in microtiter wells precoated control IgG1, anti-CD81, or anti-CD56 antibody at 1 μg/ml of each antibody, 5 μg/ml anti-E2, or immobilized E2 (1 μg/ml anti-E2/E2) for 30 min before addition of 51Cr-labeled K-562 (104 cells per well). Effector:target cell ratios of 20, 10, 5, and 2.5 were used in each experiment. Spontaneous releases for K-562 were always below 10%. Specific lysis is presented as mean percentage ± SD of duplicate samples. Data are representative of six independent experiments using different cell preparations.
Mentions: To determine whether cross-linking of CD81 can modulate NK cell–mediated cytotoxicity, freshly isolated and purified NK cells were incubated for 30 min in microtiter wells precoated with one of the following: (i) isotype matched control IgG1; (ii) anti-CD81; (iii) anti-CD56; (iv) anti-E2; or (v) immobilized E2. Non-MHC–restricted cytotoxic activity was then assessed against K562 tumor cells. A representative experiment is presented in Fig. 5 . No alteration in NK cell cytotoxic activity was observed when CD56 was cross-linked on NK cells or when NK cells were exposed to immobilized control IgG1 or mAb to E2. However, the cross-linking of CD81 on NK cells via either immobilized E2 or anti-CD81 resulted in a significant reduction in the cytolytic activity. Identical results were also observed when assessing IL-2–activated NK cells (data not presented).

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