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And the Innate Immune System Interaction of the Hepatitis B Core Interaction of the Hepatitis B Core Antigen and the Innate Immune System Byung O. Lee, Amy Tucker, Lars Frelin, Matti Sallberg, Joyce Jones, Cory Peters, Janice Hughes, David Whitacre, This information is current as Bryan Darsow, Darrell L. Peterson and David R. Milich of September 24, 2021. J Immunol 2009; 182:6670-6681; ; doi: 10.4049/jimmunol.0803683 http://www.jimmunol.org/content/182/11/6670 Downloaded from References This article cites 51 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/182/11/6670.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Interaction of the Hepatitis B Core Antigen and the Innate Immune System1 Byung O. Lee,* Amy Tucker,* Lars Frelin,* Matti Sallberg,† Joyce Jones,* Cory Peters,* Janice Hughes,* David Whitacre,*‡ Bryan Darsow,*‡ Darrell L. Peterson,§ and David R. Milich2* Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4؉ T cells than splenic) B2 cells. This was demonstrated by direct HBcAg-biotin-binding studies and by HBcAg-specific T cell activation in vitro in cultures of naive HBcAg-specific T cells and resting B cell subpopulations. The inability of DC to function as APCs for exogenous HBcAg relates to lack of uptake of HBcAg, not to processing or presentation, because HBcAg/anti-HBc immune complexes can be efficiently presented by DC. Furthermore, HBcAg-specific CD4؉ and CD8؉ T cell priming with DNA encoding HBcAg does not Downloaded from require B cell APCs. TLR activation, another innate immune response, was also examined. Full-length (HBcAg183), truncated ␬ (HBcAg149), and the nonparticulate HBeAg were screened for TLR stimulation via NF- B activation in HEK293 cells expressing human TLRs. None of the HBc/HBeAgs activated human TLRs. Therefore, the HBc/HBeAg proteins are not ligands for human TLRs. However, the ssRNA contained within HBcAg183 does function as a TLR-7 ligand, as demonstrated at the T and B cell levels in TLR-7 knockout mice. Bacterial, yeast, and mammalian ssRNA encapsidated within HBcAg183 all function as TLR-7 ligands. http://www.jimmunol.org/ These studies indicate that innate immune mechanisms bridge to and enhance the adaptive immune response to HBcAg and have important implications for the use of hepadnavirus core proteins as vaccine carrier platforms. The Journal of Immunology, 2009, 182: 6670–6681. he hepatitis B virus (HBV)3 core gene encodes two tially primes Th1 cells, whereas HBeAg preferentially primes Th2 polypeptides. Initiation of translation at the first start cells (3); HBcAg-specific Th cells mediate anti-envelope as well as T codon (AUG) results in a 25-kDa precore protein that is anti-HBc Ab production (4); and HBcAg is an effective carrier secreted as HBeAg after removal of 19 residues of the leader se- platform for heterologous epitopes (5). These characteristics are quence and 34 C-terminal amino acids. Initiation of translation at unique to and require the particulate structure of the HBcAg. A by guest on September 24, 2021 the second AUG leads to the synthesis of a 183-aa, 21-kDa protein number of hypotheses have been suggested to explain the en- that assembles to form 27-nm particles that comprise the virion hanced immunogenicity of HBcAg relative to HBeAg and to other nucleocapsid (hepatitis B core (HBc) Ag). Although HBeAg and particulate Ag. We have previously suggested that the orientation HBcAg are serologically distinct, these Ag are cross-reactive at the of the array of protein spikes distributed over the surface of the level of Th cell recognition because they are colinear throughout HBcAg shell may be optimal for cross-linking BCR and up-reg- most of their primary sequence. The HBcAg possesses unique im- ulation of costimulatory molecules (6), especially because the munologic features. For example, HBcAg can function as both a T dominant B cell epitopes are positioned at the tip of the spikes (7, cell-independent and a T cell-dependent Ag (1); HBcAg is ϳ1000- 8). Furthermore, we have previously reported that B cells rather fold more immunogenic than the HBeAg (2); HBcAg preferen- than non-B cell professional APCs such as dendritic cells or mac- rophages (DC/M␾) act as the primary APCs for HBcAg, which may explain its enhanced immunogenicity especially in terms of *Vaccine Research Institute of San Diego, San Diego, CA 92109; †Karolinska Insti- Ab production (6). Other investigators have suggested that the tutet, Clinical Microbiology, Karolinska University Hospital Huddinge, Stockholm, Sweden; ‡VLP Biotech, San Diego, CA 92109; and §Virginia Commonwealth Uni- binding of the protamine-like C terminus of HBcAg to cell mem- versity, Department of Biochemistry, Richmond, VA 23298 brane heparan sulfates (HS) or HS and chondroitin sulfates may Received for publication November 3, 2008. Accepted for publication March play a role in the enhanced immunogenicity of HBcAg (9, 10). An 14, 2009. interaction between HBcAg and TLR-2 has been proposed (9). It The costs of publication of this article were defrayed in part by the payment of page has also been suggested that contaminating TLR-4 and TLR-2 li- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. gands present in Escherichia coli-derived HBcAg may explain its 1 This work was supported by National Institutes of Health Grants R01 AI049730 and enhanced immunogenicity (11, 12). Lastly, the presence of encap- R01 AI20720 and grants from the Swedish Cancer Foundation. L.F. was supported by sidated ssRNA bound to the protamine-like domain within full- grants from Erik and Edith Fernstro¨ms Foundation and Gålo¨Foundation/Gemzeu´s length rHBcAg produced in E. coli or yeast expression systems has Foundation. been shown to enhance Th1-type immune responses (13). 2 Address correspondence and reprint requests to Dr. David R. Milich, Vaccine Re- search Institute of San Diego, 3030 Bunker Hill Street, Suite 300, San Diego, CA In an attempt to clarify or consolidate these disparate hypothe- 92109. ses, we examined Ag presentation of the HBcAg in vitro and in 3 Abbreviations used in this paper: HBV, hepatitis B virus; BMDC, bone marrow- vivo in detail to determine the ability of B cell subpopulations and derived dendritic cell; DC, dendritic cell; HS, heparan sulfate; KO, knockout; M␾, DC/M␾ cells to function as primary APCs for either exogenous or macrophage; Tg, transgenic. intracellular HBcAg particles. Furthermore, the possible role of Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 HBcAg-specific TLR-mediated activation of APCs was explored. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803683 The Journal of Immunology 6671 These studies reveal the involvement of the innate immune system Biotinylation of HBcAg150C in a rather unique APC pathway for exogenous HBcAg particles, rHBcAg150C (2 mg/ml) in 1.0 ml of PBS containing 1 mM EDTA was which is dependent on the mode of immunization. mixed with 100 ␮l of a biotin-N-(6-(biotinamido)hexyl)-3Ј-(2Ј-pyridyl- dithio)-propionamide stock solution (4 mM; Pierce) and vortexed, and the Materials and Methods reaction mixture was incubated for2hatroom temperature. Excess re- agents were removed by dialysis against PBS. Based on the absorbance Mice change at 343 nm, the biotin reacted with between 0.5 and 1 cysteine/ C57BL/10 (B10), B10.S, and 7/16-5 TCR-transgenic (Tg) mice were ob- monomer (240 monomers/particle). tained from the breeding colony of the Vaccine Research Institute of San Immunization protocols Diego. The B cell knockout (KO; ␮MT) mice originally produced by K. Rajewsky (14) were backcrossed onto B10, B10.S, and 7/16-5 TCR-Tg For protein immunization with HBcAg/WHcAg, groups of three to five backgrounds. The TLR-7KO mice were obtained from R. Flavell (Yale female mice were injected i.p. with 10–20 ␮g of protein either in saline or University, New Haven, CT) and bred at the Vaccine Research Institute of emulsified in CFA or IFA for both Ab production and T cell experiments. San Diego. The C3H.HeJ and C3H.HeSn mice and the CBA/J and CBA/N For DNA immunization, groups of 5–10 female mice were injected with (xid) mice were obtained from The Jackson Laboratory. All animal care 100 ␮g of plasmid DNA in PBS i.m. in the tibialis cranialis muscle. Mice was performed according to National Institutes of Health standards as set were boosted at 4 wk. For immunization with the RBL-5/C tumor cell line, forth in the Guide for the Care and Use of Laboratory Animals (1996). 5 ϫ 106 RBL-5/C tumor cells were given s.c. Recombinant proteins and synthetic peptide ELISA for detection of murine Abs Full-length rHBcAg183 of the ayw subtype was produced in E.
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