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Vaccine Immunity As a Novel Adjuvant in DNA Responses Through Ag85B of Mycobacteria Elicits Effective CTL Responses through Activation of Robust Th1 Immunity as a Novel Adjuvant in DNA Vaccine This information is current as of October 5, 2021. Shiki Takamura, Kazuhiro Matsuo, Yutaka Takebe and Yasuhiro Yasutomi J Immunol 2005; 175:2541-2547; ; doi: 10.4049/jimmunol.175.4.2541 http://www.jimmunol.org/content/175/4/2541 Downloaded from References This article cites 55 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/175/4/2541.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 October 5, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ag85B of Mycobacteria Elicits Effective CTL Responses through Activation of Robust Th1 Immunity as a Novel Adjuvant in DNA Vaccine1 Shiki Takamura,*† Kazuhiro Matsuo,‡¶ Yutaka Takebe,§ and Yasuhiro Yasutomi2† CD4؉ T cells play a crucial role in CTL generation in a DNA vaccination strategy. Several studies have demonstrated the requirement of CD4؉ T cells for the induction of a sufficient immune response by coadministrating DNAs. In the present study we investigated the effectiveness of Ag85B of mycobacteria, which is known to be one of the immunogenic proteins for Th1 development, as an adjuvant of a DNA vaccine. HIV gp120 DNA vaccine mixed with Ag85B DNA as an adjuvant induced HIV gp120-specific Th1 responses, as shown by delayed-type hypersensitivity, cytokine secretion, and increasing HIV-specific CTL responses. Moreover, these responses were enhanced in mice primed with Mycobacterium bovis bacillus Calmette-Gue´rin before immunization of HIV DNA vaccine mixed with Ag85B DNA. Furthermore, these immunized mice showed substantial reduction Downloaded from of HIV gp120-expressing recombinant vaccinia virus titers compared with the titers in other experimental mice after recombinant vaccinia virus challenge. Because most humans have been sensitized by spontaneous infection or by vaccination with mycobacteria, these findings indicate that Ag85B is a promising adjuvant for enhancing CTL responses in a DNA vaccination strategy. The Journal of Immunology, 2005, 175: 2541–2547. he use of adjuvant in vaccination is thought to be useful an appropriate molecule as an adjuvant for the induction of an http://www.jimmunol.org/ for enhancing the immune responses to various pathogens effective CTL response by the activation of CD4ϩ T cells. T and tumors. One of the major advantages of plasmid DNA Mycobacterium bovis bacillus Calmette-Gue´rin (BCG),3 a cur- vaccination is the induction of MHC class I-restricted CTL re- rently available vaccine to prevent tuberculosis, is thought to have sponses through endogenous production of an Ag similar to viral powerful immunogenic adjuvant activity that augments cell-medi- infection (1). However, plasmid DNA immunization does not fully ated immune responses by induction of several Th1 cytokines (8). elicit cellular immune responses against infectious pathogens in It is also well known that CFA, which contains heat-killed myco- some cases. Unlike viral infection, generation of CTLs after DNA bacteria, augments immune responses by activating Th cells. How- vaccination appears to be critically dependent on functions of ever, the specific proteins that elicit Th1 immunity of BCG are not CD4ϩ T cells, such as secretion of Th1 cytokines, which facilitate clear. One immunogenic protein that can induce a strong Th1-type by guest on October 5, 2021 CTL expansion and activity (2), and activation of professional immune response in hosts sensitized by BCG is Ag85B (also APCs through CD40-CD40L interaction to increase the expression known as ␣ Ag or MPT59) (9). Ag85B belongs to the Ag85 fam- of costimulatory molecules (3–5). Accordingly, simultaneous ac- ily, which participates in cell wall mycolic acid synthesis (10). tivation of CD4ϩ T cells, especially Th1 cells, during priming is a Moreover, Ag85B is one of most dominant protein Ags secreted promising strategy for the generation of substantial CTL responses from all mycobacterial species, shows extensive cross-reactivity when using a noninflammatory Ag expression system. In many between different species, and has been shown to induce substan- cases, some helper epitopes are already present in a DNA vaccine, tial Th cell proliferation and vigorous Th1 cytokine production in and epitope-specific CD4ϩ Th cell responses are induced after humans and mice infected with mycobacterial species, including vaccination. However, because CD4ϩ T cell help for CTL gener- individuals vaccinated with BCG (9). We previously showed that ation does not require a pathogen including a CTL epitope, patho- inoculation of Ag85B-transfected tumor cells enhances the immu- gen-specific CD4ϩ T cell responses are not necessary for eliciting nogenicity of tumor-associated Ags and elicits a strong tumor- pathogen-specific CTL immunity (6, 7). This prompted us to use specific CTL response (11). In the present study we evaluated the effectiveness of Ag85B from Mycobacterium kansassi as an adju- vant for enhancing cellular immune responses induced by DNA vaccine. *Japanese Foundation for AIDS Prevention, Tokyo, Japan; †Department of Bioregu- lation, Mie University School of Medicine, Mie, Japan; ‡Vaccine Research and De- velopment Group and §Laboratory of Molecular Virology and Epidemiology, AIDS Materials and Methods Research Center, National Institute of Infectious Disease, Tokyo, Japan; and ¶Japan Mice Science and Technology, Saitama, Japan Received for publication February 25, 2005. Accepted for publication May 31, 2005. In mice, unlike humans, studies using inbred and congenic strains have demonstrated different fastness against BCG infection among each strain The costs of publication of this article were defrayed in part by the payment of page (12). To give resistance to BCG infection, BALB/c (BCG-susceptible charges. This article must therefore be hereby marked advertisement in accordance ϫ d/k with 18 U.S.C. Section 1734 solely to indicate this fact. strain) C3H/HeN (BCG-resistant strain; CC3HF1, H-2 ) female mice were used in this study. The mice were housed at the Laboratory Animal 1 This work was supported by Health Science Research Grants from the Ministry of Center of Mie University School of Medicine. Health, Labor, and Welfare of Japan and the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 2 Address correspondence and reprint requests to Dr. Yasuhiro Yasutomi, Department 3 Abbreviations used in this paper: BCG, Mycobacterium bovis bacillus Calmette- of Bioregulation, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie Gue´rin; DC, dendritic cell; DTH, delayed-type hypersensitivity; FN, fibronectin; 514-8507, Japan. E-mail address: [email protected] MMC, mitomycin C; rVV, recombinant vaccinia virus. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 2542 Ag85B ELICITS CTL RESPONSES AS A NOVEL ADJUVANT Plasmid primers corresponding to each TLR were used: 5Ј-ATGGCAGAAGAT GTGTCCG-3Ј and 5Ј-GTCACCATGGCCAATGTAGG-3Ј for TLR2, 5Ј- A highly efficient mammalian expression vector, pJW4303, was used for TGGATTCTTCTGGTGTCTTCC-3Ј and 5Ј-AGTTCTTCACTTCGCAA efficient expression of HIV env gp120 of the NL432 strain (pJWNL432) CGC-3Ј for TLR3, 5Ј-CTGGCATCATCTTCATTGTCC-3Ј and 5Ј- (13). The Ag85B expression vector pcDNA-Ag85B has been constructed GCTTAGCAGCCATGTGTTCC-3Ј for TLR4, 5Ј-CAGAACCTTCCTG by cloning a PCR product that possesses an Ag85B of M. kansasii open GCTATTGC-3Ј and 5Ј-AGAGGTTGACCAGACCTTGG-3Ј for TLR9, reading frame lacking a signal sequence into KpnI-ApaI sites of pcDNA 3.1 and 5Ј-AGAAGAGCTATGAGCTGCCTGACG-3Ј and 5Ј-CTTCTG (11). CATCCTGTCAGCAATGCC-3Ј for ␤-actin. Peptide synthesis Generation of CTL effector cells The peptides used in this study were an HIV-1 env helper epitope (315– Effector cells were derived from spleen cells as precursor CTLs. CD8ϩ T 329; RIQRGPGRAFVTIGK; p18) and CTL epitope (318–327; RG- cells were purified with anti-CD8 magnetic beads (Miltenyi Biotec) by PGRAFVTI; p18-I10) in association with the class II MHC molecule I-Ad positive selection according to the recommended protocol (MACS system). and the class I MHC molecule H-2Dd, respectively (14). Aliquots of 1 ϫ 106 CD8ϩ T cells were cocultured with 5 ϫ 106 MMC- treated autologous spleen cells labeled with p18-I10 peptide at 37°C in a Priming to BCG 5% CO2 atmosphere. Two days after stimulation, human rIL-2 (Shionogi) Six- to 8-wk-old female mice were primed to BCG by i.p. inoculation of was added to all wells at a final concentration of 5 ng/ml. The effector cells 0.01 mg (dry weight) of BCG (Japan BCG Laboratory). generated were harvested after 5 days of culture. Immunization Cytotoxicity assay MHC-matched (A20.2j) and unmatched (FBL-3) target cells (2 ϫ 106) Four weeks after BCG priming, groups of mice were i.m. injected four were incubated at 37°C in a 5% CO atmosphere with or without 10 ␮g/ml times with 100 ␮g of pJWNL432 mixed with or without 100 ␮gof 2 p18-I10 peptide for 16 h. Then the target cells were washed and labeled Downloaded from pcDNA-Ag85B, and then the site of inoculation was immediately given an with 51Cr. The 51Cr-labeled target cells were incubated for 5 h with effector electric pulse by an Electric Square Porator (T820; BTX) to express both cells.
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