MPLA-coated hepatitis B virus surface antigen (HBsAg) nanocapsules induce vigorous T cell responses in cord blood derived human T cells

ABSTRACT Hepatitis B virus surface antigen (HBsAg) is a complex macromolecular particle composed of glycoproteins and lipids. The latter, representing 25% of the particle mass, are of host origin and determine the solubility, stability, and, indirectly, B-cell immunogenicity of HBsAg. HBsAg is a T-cell-dependent immunogen that does not elicit a detectable humoral immune response in 5% of HBsAg vaccine recipients and in most subjects suffering from chronic hepatitis B. We investigated the influence of the lipid content on the antigenicity of the particle. Lipids were partially removed from HBsAg by treatment with β-d-octyl glucoside and density centrifugation. Sham treatment consisted of density centrifugation of HBsAg only. We compared the in vitro proliferative responses of established T-cell lines and nonfractionated peripheral blood mononuclear cells (PBMC) from HBsAg vaccinees and chronic HBV patients when stimulated with partially delipidated HBsAg, untreated HBsAg, or sham-treated HBsAg. In all experiments, delipidated HBsAg turned out to be 10 to 100 times more antigenic than its untreated or sham-treated counterpart. Remarkably, PBMC from vaccine nonresponders or chronic HBV patients displayed a proliferative response towards delipidated HBsAg, whereas native HBsAg never induced a response. A series of control experiments demonstrated that this enhancement of T-cell antigenicity was HBsAg specific and directly linked to lipid extraction. Nonspecific adjuvant effects of any kind could be ruled out. In vivo evaluation in mice demonstrated that delipidated particles lose most of their B-cell antigenicity. However, when native and delipidated particles were mixed, these mixtures induced equal or slightly superior anti-HBs responses to those induced by the same quantity of native HBsAg alone. In conclusion, our data show that partial delipidation of HBsAg strikingly increases the T-cell antigenicity of this unique viral antigen.

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Effects of T cell immunoglobulin and mucin domain-containing molecule-3 signaling molecule on human monocyte-derived dendritic cells with hepatitis B virus surface antigen stimulation in vitro

Molecular Medicine Reports ◽

10.3892/mmr.2016.4815 ◽

2016 ◽

Vol 13 (3) ◽

pp. 2785-2790 ◽

Cited By ~ 3

Author(s):

ZHENJUN YU ◽

TING JIANG ◽

MIN ZHU ◽

KECHUAN PAN ◽

FEI YAN ◽

...

Keyword(s):

Dendritic Cells ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Surface Antigen ◽

Human Monocyte ◽

Virus Surface ◽

Antigen Stimulation ◽

B Virus

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Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice

The Journal of Immunology ◽

10.4049/jimmunol.166.2.1389 ◽

2001 ◽

Vol 166 (2) ◽

pp. 1389-1397 ◽

Cited By ~ 57

Author(s):

Alessandro D. Sette ◽

Carla Oseroff ◽

John Sidney ◽

Jeff Alexander ◽

Robert W. Chesnut ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Transgenic Mice ◽

Surface Antigen ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Virus Surface ◽

Virus Surface Antigen ◽

B Virus

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Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of Hepatitis B Virus-Specific CD8+T Cell Responses

Journal of Virology ◽

10.1128/jvi.00920-18 ◽

2018 ◽

Vol 92 (21) ◽

Cited By ~ 7

Author(s):

Yasuhiro Murata ◽

Keigo Kawashima ◽

Knvul Sheikh ◽

Yasuhito Tanaka ◽

Masanori Isogawa

Keyword(s):

T Cells ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Antigen Presentation ◽

Hematopoietic Cells ◽

T Cell Responses ◽

Cross Presentation ◽

Cell Responses ◽

B Virus

ABSTRACTCD8+T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8+T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8+T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8+T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8+T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8+T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8+T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8+T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8+T cells are primarily dependent on hepatocellular antigen presentation.IMPORTANCEHepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8+T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8+T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8+T cells. However, this notion has not been tested for HBV-specific CD8+T cells. In this study, we show that HBV-specific CD8+T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8+T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8+T cell responses.

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