Developmdent of BCG vaccines based on ehausted T cell re-activation

• Project/Area Number: 26293098
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Kyushu University
• Principal Investigator: yoshikai yasunobu 九州大学, 生体防御医学研究所, 教授 (90158402)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 細菌学 / BCG / IL-21 / IL-7 / ワクチン / T細胞 / 感染症 / 細菌 / 免疫学 / 微生物

Outline of Final Research Achievements

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine confers incomplete protection against tuberculosis because it is not effective for inducing long-term immunity. Therefore, it is urgently required to develop improved vaccines. We found that IL-7 and IL-21 are pleiotropic common cytokines that affect IL-17+γδT cells and CD8+T cells, respectively. Based on these results, we examined the effects of recombinant BCG secreting fusion protein Ag85B/IL-7, or IL-21 (rBCG-Ag85B-IL7, rBCG-Ag85B-IL21) on cell-mediated immune responses against BCG. The levels of effector CD8+ T cells were significantly higher butexhausted CD8+ T cells were lower after immunization with rBCG-Ag85B-IL21 compared with rBCG-Ag85B. The levels of IL-17+γδ T cells and CD4+ Th1 cells were higher in rBCG-Ag85B-IL7-immunized mice than rBCG-Ag85B-immunized mice. rBCG-Ag85B-IL-7 or IL-21 vaccination capable of inducing long-term efficient immunity might be used as an effective vaccine for tuberculosis.

Research Products

• [Journal Article] Recombinant Mycobacterium bovis Bacillus Calmette-Guerin expressing IL-7-Ag85B fusion protein enhances IL-17A-producing innate γδ T cells. (2016)
  • Author(s): Hatanoa S., Tamura T. Umemura M., Matsuzaki G., Ohara N., and Yoshikai Y.
  • Journal Title: Vaccine. Volume: 34 Issue: 22 Pages: 2490-2495
  • DOI: 10.1016/j.vaccine.2016.03.096
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection (2016)
  • Author(s): Toyonaga K, Torigoe S, Motomura Y, Kamichi T, Hayashi JM, Morita YS, Noguchi N, Chuma Y, Kiyohara H, Matsuo K, Tanaka H, Nakagawa Y, Sakuma T, Ohmuraya M, Yamamoto T, Umemura M, Matsuzaki G, Yoshikai Y, Yano I, Miyamoto T, Yamasaki S.
  • Journal Title: Immunity Volume: 45 Issue: 6 Pages: 1245-1257
  • DOI: 10.1016/j.immuni.2016.10.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two types of IL-17A-producing γδ T cells in protection against pulmonary infection with Klebsiella pneumoniae (2016)
  • Author(s): Murakami T., Hatano S., Yamada H., Iwakura Y., Yoshikai Y.
  • Journal Title: J. Infect.Dis. Volume: 214 Issue: 11 Pages: 1752-1761
  • DOI: 10.1093/infdis/jiw443
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-21 inhibits IL-17A-producing γδ T cell response after infection with Bacillus Calmette-Guerin via induction of apoptosis (2016)
  • Author(s): Huang Y., Matsumura Y., Hatano, S., Noguchi N., Murakamia, T., Iwakura Y., Sun X., Oharad N., Yoshikai Y.
  • Journal Title: Innate Immun. Volume: 22 Issue: 8 Pages: 588-597
  • DOI: 10.1177/1753425916664125
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice (2016)
  • Author(s): Wang, Y. Jiang, X., Zhu, J., Yue, D., Zhang, X., Wang, X., You, Y., Wang, B., Xu, Y., Lu, C, Sun, X., Yoshikai Y.
  • Journal Title: Sci. Rep. Volume: 22 Issue: 1 Pages: 31881-31881
  • DOI: 10.1038/srep31881
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interleukin-21-signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice (2016)
  • Author(s): Sakuraba K., Oyamada A., Fujimura K., Spolski R., Iwamoto Y., Leonard I.W., Yoshikai Y., Yamada H.
  • Journal Title: Arthritis Research & Therap. Volume: 17 Issue: 1 Pages: 188-188
  • DOI: 10.1186/s13075-016-1086-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Equol inhibits prostate cancer growth via degradation of the androgen receptor by Skp2. (2016)
  • Author(s): Itsumi M, Shiota M, Takeuchi A, Kashiwagi E, Inokuchi J, Tatsugami K, Kajioka S, Uchiumi T, Naito S, Eto M, Yokomizo A.
  • Journal Title: Cancer Sci Volume: in press Pages: 327-331
  • DOI: 10.1016/j.intimp.2016.03.007
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Antitumor activity of recombinant Bacille Calmette-Guerin secreting interleukin-15-Ag85B fusion protein against bladder cancer. (2016)
  • Author(s): Takeuchi A., , Eto M., Yamada H., Shita M., Tatsugami K., Kiyoshima K., Inokuchi J., Itsumi M., Takahashi R., Yokomizo A., Ohara N. Yoshikai Y.
  • Journal Title: Int Immunopharmacol. Volume: 16;35 Pages: 327-331
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Expressing IL-7-Ag85B Fusion Protein Enhances IL-17A-producing Innate γδ T Cells. (2016)
  • Author(s): Hatanoa S. , Tamurab, T. Umemura M., Matsuzaki G., Ohara N., and Yoshikai Y.
  • Journal Title: Vaccine Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dermal Vγ4+ γδ T cells possess a migratory potency to the draining lymph nodes and modulate CD8+ T cell activity through TNF-α production. (2015)
  • Author(s): Nakamizo S., Egawa G., Tomura M., Sakai S., Tsuchiya S., Kitoh A., Honda T., Otsuka A., Nakajima S., Dainichi T., Tanizaki H., Mitsuyama M., Sugimoto Y., Kawai K., Yoshikai Y., Miyachi Y. and Kabashima K.
  • Journal Title: J. Invest. Dermatology. Volume: 135 Pages: 1007-15
  • NAID: 120005621945
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An enhancer of the IL-7 receptor alpha-chain locus controls IL-7 receptor expression and maintenance of peripheral T cells. (2015)
  • Author(s): Abe, A., Tani-ichi, S., Shitara, S., Cui, G., Yamada, H., Miyachi, H., Kitano, S., Hara, T., Abe, R., Yoshikai, Y., and Ikuta, K.
  • Journal Title: J. Immunol. Volume: 195 Pages: 3129-38
  • Peer Reviewed / Open Access
• [Journal Article] IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells. (2015)
  • Author(s): Akitsu, A., Ishigame, H., Kakuta, S., Chung SH, Ikeda, S., Shimizu, K., Kubo, S., Liu, Y., Umemura, M., Matsuzaki, G., Yoshikai, Y., Saijo, S., and Iwakura Y.
  • Journal Title: Nature Communication Volume: 6 Pages: 7464-7464
  • Peer Reviewed / Open Access
• [Journal Article] A genome-wide analysis identifies a notch-RBP-Jκ-IL-7Rα axis that controls IL-17-producing γδ T cell homeostasis in mice. (2015)
  • Author(s): Nakamura M, Shibata K, Hatano S, Sato T, Ohkawa Y, Yamada H, Ikuta K, and Yoshikai Y.
  • Journal Title: J.Immunol Volume: 194 Pages: 243-251
  • Peer Reviewed
• [Journal Article] Tyk2-dependent bystander activation of conventional and non-conventional Th1 cell subsets contributes to innate host defense against Listeria monocytogenes infection. (2014)
  • Author(s): Hashiguchi T., Oyamada A., Sakuraba K., Iwamoto Y., Yoshikai, Y. and Yamada H.
  • Journal Title: J.Immunol. Volume: 192 Pages: 4739-4747
  • Peer Reviewed
• [Journal Article] IFN-γ-producing and IL-17-producing γδ T cells differentiate at distinct developmental stages in murine fetal thymus. (2014)
  • Author(s): Shibata K. , Yamada H., Nakamura M., Katsuragi Y., Kominami R. and Yoshikai Y.
  • Journal Title: J.Immunol. Volume: 192 Pages: 2210-2218
  • Peer Reviewed
• [Presentation] γδ型 T細胞-原始的T細胞として- (2017)
  • Author(s): 吉開泰信
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台市
  • Year and Date: 2017-03-19
  • Invited
• [Presentation] A critical role of primitive γδ T cells developing (from DN2a stage) independently of Bcl11b in early host defense. (2016)
  • Author(s): Shinya Hatano, Tesshin Murakami, Yumiko Matsumura, Hisakata Yamada, Yasunobu Yoshikai
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] CD153-CD30 interaction is involved in immunosenescence of T cells and spontaneous germinal center reactions. (2016)
  • Author(s): Yuji Fukushima, Hisakata Yamada, Yasunobu Yoshikai, Nagahiro Minato, Masakazu Hattori
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] In vivo blockade of T cell development defines developmental pathways of intraepithelial lymphocytes in mice. (2016)
  • Author(s): Surenchimeg Mondoon, Kensuke Shibata, Yasunobu Yoshikai
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] Recognition of mycobacterial lipid by Dendritic cell immunoactivating receptor. (2016)
  • Author(s): Kenji Toyonaga, Shota Torigoe, Yoshitomo Motomura, Takane Kamichi, Kazuhiro Matuo, Yasunobu Yoshikai, Sho Yamasaki.
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] Bcl11b非依存性primitive γδT cellによる感染防御機構 (2016)
  • Author(s): 畑野晋也、村上哲晋、野口直人、松村友美子、山田久方、吉開泰信
  • Organizer: 第27回日本生体防御学会学術総会
  • Place of Presentation: 福岡市
  • Year and Date: 2016-07-07
• [Presentation] 異なる活性化経路をもつ2種類のIL-17A産生γδT細胞が、肺炎桿菌に対する感染防御に重要な役割を果たす。 (2016)
  • Author(s): 村上哲晋、畑野晋也、山田久方、岩倉洋一郎、吉開泰信
  • Organizer: 第27回日本生体防御学会学術総会
  • Place of Presentation: 福岡市
  • Year and Date: 2016-07-07
• [Presentation] γδ型 T細胞と生体防御 (2016)
  • Author(s): 吉開泰信
  • Organizer: 第27回日本生体防御学会学術総会
  • Place of Presentation: 福岡市
  • Year and Date: 2016-07-07
  • Invited
• [Presentation] Newly identified BCL11b-independent γδ T cell subset in the periphery in mice. (2016)
  • Author(s): 畑野晋也、村上哲晋、松村友美子、山田久方、吉開泰信
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2016-03-23
• [Presentation] Two types of IL-17A-producing γδ T cells play critical roles against Klebsiella pneumoniae. (2016)
  • Author(s): 村上哲晋、畑野晋也、山田久方、岩倉洋一郎、吉開泰信
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2016-03-23
• [Presentation] Analysis of a novel subset of IFN-γ-producing DN2a γδT cells in the periphery of mice. (2015)
  • Author(s): Shinya Hatano, Tesiin Murakami, Hisakata Yamada, and Yasunobu Yoshikai
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2015-11-18
• [Presentation] Two types of IL-17A-producing γδ T cells play critical roles in protection against pulmonary infection with Klebsiella pneumoniae in different activation manners. (2015)
  • Author(s): Tesshin Murakami, Shinya Hatano, Naoto Noguchi, Yasunobu Yoshikai
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2015-11-18
• [Presentation] マウスにおける新規IFN-γ産生γδ細胞サブセットの解析 (2015)
  • Author(s): 畑野晋也、柴田健輔、山田久方、吉開泰信
  • Organizer: 第26回日本生体防御学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-10
• [Presentation] IL-17A+ γδ cells are required for the protection against Klebsiella pneumonia at infant stage. (2015)
  • Author(s): 村上哲晋, 畑野晋也,柴田健輔, 山田久方, 吉開泰信
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 岐阜市
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] Development of a recombinant BCG expressing murine IL-7 as a novel vaccine against tuberculosis. (2015)
  • Author(s): 畑野晋也, 柴田健輔, 山田久方, 大原直也, 田村敏生, 吉開泰信
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 岐阜市
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] IFN-γ-producing and IL-17-producing γδ T cells differentiate at distinct developmental stages in murine fetal thymus. (2014)
  • Author(s): Shinya Hatano, Kensuke Shibata, Hisakata Yamada, Yasunobu Yoshikai.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2014-12-10 – 2014-12-12
• [Book] ウイルスによる膵島細胞障害 －ウイルス糖尿病予防ワクチンの開発は可能か？－ (2017)
  • Author(s): 永淵正法、勝田仁、三根敬一朗、吉開泰信
  • Total Pages: 236
  • Publisher: 羊土社
• [Book] 次世代アジュバント開発のためのメカニズム解明と安全性評価 (2017)
  • Author(s): 吉開 泰信
  • Total Pages: 249
  • Publisher: シーエムシー出版
• [Book] 化学療法の領域「γδ型T細胞と細菌感染防御」 (2015)
  • Author(s): 吉開 泰信
  • Publisher: 医薬ジャーナル社
• [Book] 臨床免疫 アレルギー 科 「γδ型 T 細胞からのIL-17産生」 (2014)
  • Author(s): 吉開 泰信
  • Total Pages: 7
  • Publisher: 科学評論社