論文 - 松崎　吾朗

Innate and acquired immune responses to mycobacterial infections: involvement of IL-17A/IL-23 axis in protective immunity.

Umemura M, Matsuzaki G

Nihon Hansenbyo Gakkai zasshi = Japanese journal of leprosy : official organ of the Japanese Leprosy Association ( 日本ハンセン病学会 )  82 ( 3 ) 123 - 32   2013年12月

掲載種別: 研究論文（学術雑誌）

　概要を見る

未だに世界中の人々を死に至らしめる最も大きな原因は感染症であり、病原性マイコバクテリアの代表である結核菌の感染も再び猛威を拡げ、感染症研究に大きな期待が掛けられている。結核菌感染症のなかでも特に肺結核はその発症頻度が高く、しばしば致命的な疾患に陥るにもかかわらず、肺における感染防御メカニズムは不明瞭な点が多い。この結核菌に対する免疫監視メカニズムと結核菌の病原因子の相互作用を理解し、結核菌感染症における免疫応答の分子基盤を整理および再構築することが、免疫制御による結核の予防ならびに治療法の開発に繋がると考えられる。本稿では、結核菌感染症における病原体側あるいは宿主側の視点からの感染制御メカニズムを概説すると共に、最近注目されているIL-17A/IL-23系の役割について解説する。

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A bio-nanocapsule containing envelope protein domain III of Japanese encephalitis virus protects mice against lethal Japanese encephalitis virus infection

Takeshi Miyata, Senji Tafuku, Tetsuya Harakuni, Masayuki Tadano, Nobuo Yoshimoto, Masumi Iijima, Hidenori Matsuo, Goro Matsuzaki, Shun'ichi Kuroda, Takeshi Arakawa

Microbiology and Immunology ( Wiley )  57 ( 6 ) 470 - 477   2013年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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An engineered bio-nanocapsule (BNC) comprising modified hepatitis B surface antigen L protein was used as a physical scaffold for envelope protein domain III (D3) of Japanese encephalitis virus (JEV). At the N terminus, the BNC contained a two-tandem repeat of the Z domain (ZZ) derived from Staphylococcus aureus protein A (ZZ-BNC). The Lys-rich ZZ moiety exposed on the surface of ZZ-BNC was used for chemical conjugation with the JEV D3 antigen, which had been expressed and purified from Escherichia coli. Immunization of mice with D3 loaded on the surface of ZZ-BNC (ZZ-BNC:D3) augmented serum IgG response against JEV and increased protection against lethal JEV infection. The present study suggests that innocuous recombinant antigens, when loaded on the surface of ZZ-BNC, can be transformed to immunogenic antigens. © 2013 The Societies and Wiley Publishing Asia Pty Ltd.

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A bio-nanocapsule containing envelope (E) protein domain III of Japanese encephalitis virus (JEV) protects mice against lethal JEV infection

Takeshi Miyata, Senji Tafuku, Tetsuya Harakuni, Masayuki Tadano, Nobuo Yoshimoto, Masumi Iijima, Hidenori Matsuo, Goro Matsuzaki, Shun'ichi Kuroda, Takeshi Arakawa

Microbiology and Immunology ( Wiley )    n/a - n/a   2013年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Physicochemically stable cholera toxin B subunit pentamer created by peripheral molecular constraints imposed by de novo-introduced intersubunit disulfide crosslinks.

Miyata T, Oshiro S, Harakuni T, Taira T, Matsuzaki G, Arakawa T

Vaccine ( Vaccine )  30 ( 28 ) 4225 - 32   2012年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We attempted to generate a physicochemically stable cholera toxin B subunit (CTB) by de novo-introduction of intersubunit disulfide bonds between adjacent subunits. Genes encoding double mutant CTB (dmCTB) encompassing a pair of amino acids to be replaced with cysteine residues either at the N-terminal (T1C/T92C, Q3C/T47C), C-terminal (F25C/N103C, Y76C/N103C), or at the internal et-helix region (L77C/T78C), were engineered. One mutant with the N-terminal constraint [dmCTB(T1C/T92C)], expressed as pentamer retained monosialoganglioside G(M1) (GM1) binding affinity, and exhibited robust thermostability. However, when the mutant CTB was heat-treated in the presence of a reducing agent, the thermostable phenotype was abolished, indicating the observed phenotype is due to the introduction of intersubunit disulfide bonds. The mutant CTB also exhibited a strong acid stability at a pH as low as 1.2, as well as stability against incubation with sodium dodecyl sulfate at concentrations as high as 10%. Furthermore, intranasal administration of the mutant CTB to mice induced CTB-specific serum IgG even after heat treatment, while the wildtype CTB failed to show such heat-resistant mucosal immunogenicity. This study demonstrated that an enterotoxin B subunit could be transformed into a physicochemically stable pentamer by the de novo-introduction of peripherally arranged intersubunit disulfide crosslinks, which may prove to be a useful strategy for the development of molecularly stable enterotoxin B subunit-based vaccines and delivery molecules. (C) 2012 Elsevier Ltd. All rights reserved.

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Inhibitory effects of an ellagic acid glucoside, okicamelliaside, on antigen-mediated degranulation in rat basophilic leukemia RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice.

Kuba-Miyara M, Agarie K, Sakima R, Imamura S, Tsuha K, Yasumoto T, Gima S, Matsuzaki G, Ikehara T

International immunopharmacology ( International Immunopharmacology )  12 ( 4 ) 675 - 81   2012年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Degranulation inhibitors in plants are widely used for prevention and treatment of immediate-type allergy. We previously isolated a new ellagic acid glucoside, okicamelliaside (OCS), from Camellia japonica leaves for use as a potent degranulation inhibitor. Crude extracts from leaves also suppressed allergic conjunctivitis in rats. In this study, we evaluated the in vivo effect of OCS using a pure sample and performed in vitro experiments to elucidate the mechanism underlying the extraordinary high potency of OCS and its aglycon. The IC50 values for degranulation of rat basophilic leukemia cells (RBL-2H3) were 14 nM for OCS and 3 mu M for aglycon, indicating that the two compounds were approximately 2 to 3 orders of magnitude more potent than the anti-allergic drugs ketotifen fumarate. DSCG, and tranilast (0.17, 3, and > 0.3 mM, respectively). Antigen-induced calcium ion (Ca2+) elevation was significantly inhibited by OCS and aglycon at all concentrations tested (p < 0.05). Upstream of the Ca2+ elevation in the principle signaling pathway, phosphorylation of Syk (Tyr525/526) and PLC gamma-1 (Tyr783 and Ser1248) were inhibited by OCS and aglycon. In DNA microarray-screening test, OCS inhibited expression of proinflammatory cytokines [interleukin (IL)-4 and IL-13], cytokine-producing signaling factors, and prostaglandin-endoperoxidase 2, indicating that OCS broadly inhibits allergic inflammation. During passive cutaneous anaphylaxis in mice, OCS significantly inhibited vascular hyperpermeability by two administration routes: a single intraperitoneal injection at 10 mg/kg and per os at 5 mg/kg for 7 days (p < 0.05). These results suggest the potential for OCS to alleviate symptoms of immediate-type allergy. (C) 2012 Elsevier B.V. All rights reserved.

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Merozoite surface protein-1 of Plasmodium yoelii fused via an oligosaccharide moiety of cholera toxin B subunit glycoprotein expressed in yeast induced protective immunity against lethal malaria infection in mice.

Miyata T, Harakuni T, Taira T, Matsuzaki G, Arakawa T

Vaccine ( Vaccine )  30 ( 5 ) 948 - 58   2012年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Methylotrophic yeast (Pichia pastoris) secreted cholera toxin B subunit (CUB) predominantly as a biologically active pentamer (PpCTB) with identical ganglioside binding affinity profiles to that of choleragenoid. Unlike choleragenoid, however, the PpCTB did not induce a footpad edema response in mice. Of the two potential glycosylation sites (NIT4-6 and NICT90-92) for this protein, a N-linked oligosaccharide was identified at Asn4. The oligosaccharide, presumed to extend from the lateral circumference of the CUB pentamer ring structure, was exploited as a site-specific anchoring scaffold for the C-terminal 19-kDa merozoite surface protein-1 (MSP1-19) of the rodent malaria parasite, Plasmodium yoelii. Conjugation of MSP1-19 to PpCTB via its oligosaccharide moiety induced higher protective efficacy against lethal parasite infection than conjugation directly to the PpCTB protein body in both intranasal and subcutaneous immunization regimes. Such increased protection was potentially due to the higher antigen loading capacity of CUB achieved when the antigen was linked to the extended branches of the oligosaccharide. This might have allowed the antigen to reside in more spacious molecular environment with less steric hindrance between the constituent molecules of the fusion complex. (C) 2011 Elsevier Ltd. All rights reserved.

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Interleukin-17A is involved in enhancement of tumor progression in murine intestine.

Oshiro K, Kohama H, Umemura M, Uyttenhove C, Inagaki-Ohara K, Arakawa T, Harada M, Nakae S, Iwakura Y, Nishimaki T, Matsuzaki G

Immunobiology ( Immunobiology )  217 ( 1 ) 54 - 60   2012年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Interleukin (IL)-17A is a cytokine involved in neutrophilic inflammation but the role of IL-17A in antitumor immunity is controversial because both pro- and anti-tumor activities of IL-17A have been reported. We hypothesized that constitutive expression of IL-17A in intestinal environment modifies tumor growth. To address the issue, mice were inoculated into subserosa of cecum (i.c.) with murine EL4 lymphoma expressing a model tumor antigen, and tumor growth was monitored. IL-17A-producing cells were detected both in tumor mass and in normal intestinal tissue of i.c. tumor-bearing wild type mice. Tumor size in the wild-type mice was significantly higher than that in the cecum of IL-17A gene-knockout mice. Furthermore, anti-IL-17A monoclonal antibody treatment of wild-type mice resulted in decreased tumor size in the cecum. Model tumor-antigen-specific interferon-gamma production was not modified in draining mesenteric lymph node cells in the absence or after neutralization of IL-17A. All the results suggest that constitutive expression of IL-17A in intestine enhances tumor growth, and anti-IL-17A antibody treatment is a candidate of a new anti-tumor immunotherapy against intestinal tumors. (C) 2011 Elsevier GmbH. All rights reserved.

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Tricomponent immunopotentiating system as a novel molecular design strategy for malaria vaccine development.

Miyata T, Harakuni T, Tsuboi T, Sattabongkot J, Ikehara A, Tachibana M, Torii M, Matsuzaki G, Arakawa T

Infection and immunity ( American Society for Microbiology )  79 ( 10 ) 4260 - 75   2011年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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<jats:title>ABSTRACT</jats:title> <jats:p> The creation of subunit vaccines to prevent malaria infection has been hampered by the intrinsically weak immunogenicity of the recombinant antigens. We have developed a novel strategy to increase immune responses by creating genetic fusion proteins to target specific antigen-presenting cells (APCs). The fusion complex was composed of three physically linked molecular entities: (i) a vaccine antigen, (ii) a multimeric α-helical coiled-coil core, and (iii) an APC-targeting ligand linked to the core via a flexible linker. The vaccine efficacy of the tricomponent complex was evaluated using an ookinete surface protein of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium vivax</jats:named-content> , Pvs25, and merozoite surface protein-1 of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium yoelii</jats:named-content> . Immunization of mice with the tricomponent complex induced a robust antibody response and conferred substantial levels of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content> transmission blockade as evaluated by a membrane feed assay, as well as protection from lethal <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. yoelii</jats:named-content> infection. The observed effect was strongly dependent on the presence of all three components physically integrated as a fusion complex. This system, designated the tricomponent immunopotentiating system (TIPS), onto which any recombinant protein antigens or nonproteinaceous substances could be loaded, may be a promising strategy for devising subunit vaccines or adjuvants against various infectious diseases, including malaria. </jats:p>

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[Interleukin network in pulmonary tuberculosis].

Matsuzaki G, Umemura M

Nihon rinsho. Japanese journal of clinical medicine ( 日本臨床社 )  69 ( 8 ) 1368 - 1372   2011年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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[Interleukin network in pulmonary tuberculosis].

Matsuzaki G, Umemura M

Nihon rinsho. Japanese journal of clinical medicine   69 ( 8 ) 1368 - 72   2011年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Contribution of IL-17–producing γδ T cells to the efficacy of anticancer chemotherapy

Yuting Ma, Laetitia Aymeric, Clara Locher, Stephen R. Mattarollo, Nicolas F. Delahaye, Pablo Pereira, Laurent Boucontet, Lionel Apetoh, François Ghiringhelli, Noëlia Casares, Juan José Lasarte, Goro Matsuzaki, Koichi Ikuta, Bernard Ryffel, Kamel Benlagha, Antoine Tesnière, Nicolas Ibrahim, Julie Déchanet-Merville, Nathalie Chaput, Mark J. Smyth, Guido Kroemer, Laurence Zitvogel

Journal of Experimental Medicine ( Rockefeller University Press )  208 ( 3 ) 491 - 503   2011年03月

掲載種別: 研究論文（学術雑誌）

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<jats:p>By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ–producing CD8+ αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17–producing γδ (Vγ4+ and Vγ6+) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ−/− or Vγ4/6−/− mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A–IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A−/− hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4+ αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.</jats:p>

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Interleukin-17A is required to suppress invasion of Salmonella enterica serovar Typhimurium to enteric mucosa.

Mayuzumi H, Inagaki-Ohara K, Uyttenhove C, Okamoto Y, Matsuzaki G

Immunology ( Immunology )  131 ( 3 ) 377 - 85   2010年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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P&gt;Salmonella enterica serovar Typhimurium (S. typhimurium) causes a localized enteric infection and its elimination is dependent on a T helper type 1 immune response. However, the mechanism of the protective immune response against the pathogen in gut-associated lymphoid tissue (GALT) at an early stage of the infection is not yet clarified. Here, we show that interleukin-17A (IL-17A) was constitutively expressed in GALT; it was also detected on crypt and epithelial cells of the small intestine. Neutralization of the IL-17A in the intestinal lumen exacerbated epithelial damage induced by intestinal S. typhimurium infection at an early stage of the infection. The result suggests that IL-17A has a pivotal role in the immediate early stage of protection against bacterial infection at the intestinal mucosa. As IL-17A neutralization also suppressed the constitutive localization of beta-defensin 3 (BD3), an IL-17A-induced antimicrobial peptide, at the apical site of the intestinal mucosa, it is estimated that IL-17A constitutively induces the expression of the antimicrobial peptide to kill invading pathogens at the epithelial surface immediately after the infection. In contrast, interferon-gamma is induced around 3 days after S. typhimurium infection, and its expression level increases thereafter. Taken together, the findings lead to the hypothesis that IL-17A participates in the immediate early stage of protection against S. typhimurium intestinal infection whereas interferon-gamma is important at a later stage of the infection.

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Plasmodium vivax ookinete surface protein Pvs25 linked to cholera toxin B subunit induces potent transmission-blocking immunity by intranasal as well as subcutaneous immunization.

Miyata T, Harakuni T, Tsuboi T, Sattabongkot J, Kohama H, Tachibana M, Matsuzaki G, Torii M, Arakawa T

Infection and immunity ( American Society for Microbiology )  78 ( 9 ) 3773 - 82   2010年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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<jats:title>ABSTRACT</jats:title> <jats:p> The nontoxic cholera toxin B subunit (CTB) was evaluated as a potential delivery molecule for the <jats:italic>Plasmodium vivax</jats:italic> ookinete surface protein, Pvs25. Recombinant Pvs25 was expressed as a secreted protein in the yeast <jats:italic>Pichia pastoris</jats:italic> , as a mixture of isoforms including multimers and the A and B monomers. The A isoform with the presumed native protein fold was the most abundant, accounting for more than 40% of all expressed protein. The molecularly uniform A isoform was chemically conjugated to CTB via its primary amines, and the fusion protein, retaining GM1-ganglioside affinity, was administered to BALB/c mice by the subcutaneous (s.c.) or intranasal (i.n.) route. Immunization of mice with conjugated Pvs25 without supplemental adjuvant induced antisera that specifically recognized <jats:italic>P. vivax</jats:italic> ookinetes <jats:italic>in vitro</jats:italic> . Furthermore, the antisera, when mixed with parasitized blood isolated from <jats:italic>P. vivax</jats:italic> patients from Thailand, was found to reduce parasite transmission to mosquitoes, conferring a 93 to 98% (s.c.) or a 73 to 88% (i.n.) decrease in oocyst number. Unconjugated Pvs25 alone conferred only a 23 to 60% (s.c.) or a 0 to 6% (i.n.) decrease in oocyst number. Coadministration of extraneous adjuvants, however, further enhanced the vaccine efficacy up to complete blockade. Taken together, we conclude that a weakly immunogenic Pvs25 by itself, when linked to CTB, transforms into a potent transmission-blocking antigen in both i.n. and s.c. routes. In addition, the present study is, to the best of our knowledge, the first demonstration of the immune potentiating function of CTB for a vaccine antigen delivered by the s.c. route. </jats:p>

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Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung.

Okamoto Yoshida Y, Umemura M, Yahagi A, O'Brien RL, Ikuta K, Kishihara K, Hara H, Nakae S, Iwakura Y, Matsuzaki G

Journal of immunology (Baltimore, Md. : 1950) ( The American Association of Immunologists )  184 ( 8 ) 4414 - 22   2010年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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<jats:title>Abstract</jats:title> <jats:p>Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.</jats:p>

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Suppressed induction of mycobacterial antigen-specific Th1-type CD4+ T cells in the lung after pulmonary mycobacterial infection.

Yahagi A, Umemura M, Tamura T, Kariyone A, Begum MD, Kawakami K, Okamoto Y, Hamada S, Oshiro K, Kohama H, Arakawa T, Ohara N, Takatsu K, Matsuzaki G

International immunology ( International Immunology )  22 ( 4 ) 307 - 18   2010年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Although the importance of T(h)1-type immune response in protection against mycobacterial infection is well recognized, its regulatory mechanism in the Mycobacterium tuberculosis (Mtb)-infected lung is not well characterized. To address this issue, we analyzed kinetics of induction of mycobacterial antigen-specific CD4(+) T(h)1 T cells after mycobacterial infection in P25 TCR-transgenic (Tg) mice which express TCR alpha and beta chains from a mycobacterial Ag85B-specific MHC class II A(b)-restricted CD4(+) T-cell clone. To supply normal regulatory T-cell repertoire, we transferred normal spleen T cells into the P25 TCR-Tg mice before infection. High dose subcutaneous infection with Mtb or Mycobacterium bovis bacillus Calmette-Guerin (BCG) induced P25 TCR-Tg CD4(+) T(h)1 cells within a week. In contrast, high-dose Mtb or BCG infection into the lung failed to induce P25 TCR-Tg CD4(+) T(h)1 cells at the early stage of the infection. Furthermore, low-dose Mtb infection into the lung induced P25 TCR-Tg CD4(+) T(h)1 cells on day 21 in the mediastinal lymph node but not in the lung. IL-10 was partially involved in the suppression of T(h)1 induction in the lung because pretreatment of mice with anti-IL-10 antibody resulted in increase of P25 TCR-Tg CD4(+) T(h)1 cells in the Mtb-infected lung on day 21 of the infection, whereas neutralization of transforming growth factor-beta, another important suppressive cytokine in the lung, showed no effects on the T(h)1 induction. Our data suggest that induction of anti-mycobacterial CD4(+) T(h)1 cells is suppressed in the mycobacteria-infected lung partially by IL-10.

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Accelerated induction of mycobacterial antigen-specific CD8+ T cells in the Mycobacterium tuberculosis-infected lung by subcutaneous vaccination with Mycobacterium bovis bacille Calmette-Guérin.

Begum D, Umemura M, Yahagi A, Okamoto Y, Hamada S, Oshiro K, Matsuzaki G

Immunology ( Immunology )  128 ( 4 ) 556 - 563   2009年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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P&gt;Both CD4+ and CD8+ T cells are important in protection against Mycobacterium tuberculosis infection. To evaluate the effect of vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG) on the CD8+ T-cell response to pulmonary M. tuberculosis infection, we analyzed the kinetics of CD8+ T cells specific to the mycobacterial Mtb32a(309-318) epitope, which is shared by M. tuberculosis and M. bovis BCG, in the lung of mice infected with M. tuberculosis. The CD8+ T cells were detected by staining lymphocytes with pentameric major histocompatibility complex (MHC) class I H-2Db-Mtb32a(209-318) peptide complex and were analysed by flow cytometry. Mtb32a-specific CD8+ T cells became detectable on day 14, and reached a plateau on day 21, in the lung of M. tuberculosis-infected unvaccinated mice. Subcutaneous vaccination with M. bovis BCG in the footpads induced Mtb32a-specific CD8+ T cells in the draining lymph nodes (LNs) on day 7 and their numbers further increased on day 14. When M. bovis BCG-vaccinated mice were exposed to pulmonaryinfection with M. tuberculosis 4 weeks after vaccination, the Mtb32a-specific CD8+ T cells in the infected lung became detectable on day 7 and reached a plateau on day 14, which was 1 week earlier than in the unvaccinated mice. The pulmonary CD8+ T cells from the BCG-vaccinated M. tuberculosis-infected mice produced interferon-gamma in response to Mtb32a(209-318) peptide on day 7 of the infection, whereas those of unvaccinated mice did not. The results demonstrate that induction of mycobacterial antigen-specific protective CD8+ T cells in the M. tuberculosis-infected lung is accelerated by subcutaneous vaccination with M. bovis BCG.

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Importance of murine Vdelta1gammadelta T cells expressing interferon-gamma and interleukin-17A in innate protection against Listeria monocytogenes infection.

Hamada S, Umemura M, Shiono T, Hara H, Kishihara K, Tanaka K, Mayuzumi H, Ohta T, Matsuzaki G

Immunology ( Immunology )  125 ( 2 ) 170 - 7   2008年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Murine gamma delta T cells participate in the innate immune response against infection by an intracellular pathogen Listeria monocytogenes. V delta 1(+)gamma delta T cells coexpressing V gamma 6 are a major gamma delta T-cell subpopulation induced at an early stage of L. monocytogenes infection in the livers of infected mice. To investigate the protective role of the V gamma 6/V delta 1(+)gamma delta T cells against L. monocytogenes infection, V delta 1 gene-deficient (V delta 1(-/-)) mice were analysed because these mice selectively lacked a V gamma 6/V delta 1(+)gamma delta T-cell subpopulation in the L. monocytogenes-infected liver. The V delta 1(-/-) mice showed increased bacterial burden in the liver and spleen, and decreased survival rate at an early stage of L. monocytogenes infection when compared to wild-type mice. Histological examination showed abscess-like lesions and unorganized distribution of macrophages in the liver of the V delta 1(-/-) mice but not in the wild-type mice after L. monocytogenes infection. The V gamma 6/V delta 1(+)gamma delta T cells produced interferon-gamma and interleukin-17A. All the results suggest that murine V gamma 6/V delta 1(+)gamma delta T cells control the innate protective response against L. monocytogenes infection through production of the proinflammatory cytokines interferon-gamma and interleukin-17A in the infected liver.

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IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver.

Satoru Hamada, Masayuki Umemura, Takeru Shiono, Kensho Tanaka, Ayano Yahagi, M Dilara Begum, Kiyotetsu Oshiro, Yuko Okamoto, Hisami Watanabe, Kazuyoshi Kawakami, Christina Roark, Willi K Born, Rebecca O'Brien, Koichi Ikuta, Hiromichi Ishikawa, Susumu Nakae, Yoichiro Iwakura, Takao Ohta, Goro Matsuzaki

Journal of immunology (Baltimore, Md. : 1950)   181 ( 5 ) 3456 - 63   2008年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver.

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Rapid induction of OX40 ligand on primary T cells activated under DNA-damaging conditions.

Kondo K, Okuma K, Tanaka R, Matsuzaki G, Ansari AA, Tanaka Y

Human immunology ( Human Immunology )  69 ( 9 ) 533 - 42   2008年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We have previously demonstrated that normal human T cells either tong-term repeatedly stimulated or freshly activated in vitro in the presence of TGF-beta express the cell surface T-cell costimulating molecule OX40 ligand (OX40L). To further elucidate the kinetics of OX40L expression by human T cells, we have examined whether cell proliferation was required for the expression of CX40L. Thus, normal fresh peripheral blood mononuclear cells were stimulated with immobilized anti-CD3 antibody in the presence of the DNA synthesis-blocking agents such as mitomycin C, 5-fluorouracil, or X-ray irradiation. Flow cytometric analyses demonstrated that a significant frequency of these DNA-damaged activated primary CD4(+) and CD8(+) T cells became OX40L(+) as early as 1 hour after treatment. The OX40L induction on the DNA-damaged activated T cells was inhibited by treatment with either RNA or protein synthesis inhibitors, actinomycin D, or cycloheximide, respectively. Induced OX40L on T cells was functional because it bound recombinant OX40. These data indicate that human primary T cells are programmed to rapidly express functional OX40L molecules after stimulation under DNA-damaging conditions, demonstrating that the induction of OX40L by T cells is independent of cell proliferation. The clinical implications of these new findings are discussed. (C) 2008 American Society for Histocompatibitity and Immunogenetics. Published by Elsevier Inc. All rights reserved.

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Mucosal immunization with recombinant heparin-binding haemagglutinin adhesin suppresses extrapulmonary dissemination of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in infected mice.

Kohama H, Umemura M, Okamoto Y, Yahagi A, Goga H, Harakuni T, Matsuzaki G, Arakawa T

Vaccine ( Vaccine )  26 ( 7 ) 924 - 32   2008年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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It is generally accepted that cellular immunity plays a critical role in the protection against Mycobacterium tuberculosis, an intracellular pathogen. Recently, however, an increasing number of reports indicate the important contribution of humoral immunity against mycobacterial infection. Since M. tuberculosis establishes its primary lesion in the lung, induction of humoral immunity in the airway tract by mucosal immunization regime could provide protective immunity against tuberculosis. In this study, mycobacterial heparin-binding haemagglutinin adhesin (HBHA) was used as an immunization antigen because HBHA is an essential virulence factor required for the infection of lung epithelial cells and extrapulmonary dissemination of mycobacteria. The effects of intranasal immunization with a yeast-expressed recombinant (r) HBHA co-administered with a mucosal adjuvant cholera toxin (CT) on the induction of humoral and cellular immunity were examined, and its protective efficacy against pulmonary challenge infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) was evaluated. HBHA-specific antibodies were induced in serum and airway tract of immunized mice, which specifically recognized native HBHA expressed on M. bovis BCG. Th1-type immunity against mycobacterial antigens was also enhanced in the lung of immunized mice after pulmonary BCG infection. Furthermore, the immunization suppressed bacterial load in the spleen after pulmonary BCG infection. These results indicate that systemic and local humoral immunity induced by the HBHA-based mucosal vaccine impairs extrapulmonary dissemination, thus providing immune protection against mycobacterial infection.

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