Studies on the role of Plasmodium-specific Tr27 cells in infection regulation and on their antigen recognition

• Project/Area Number: 19H03460
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49040:Parasitology-related
• Research Institution: Nagasaki University
• Principal Investigator: Yui Katsuyuki 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90274638)
• Co-Investigator(Kenkyū-buntansha): 井上 信一 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (20466030) ; 高島 英造 愛媛大学, プロテオサイエンスセンター, 准教授 (50366762) ; 木村 大輔 神戸女子大学, 健康福祉学部, 教授 (50423637)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: マラリア / T細胞 / サイトカイン / 免疫制御 / 抗原 / IL-27 / 自然免疫 / 感染防御 / 樹状細胞 / マクロファージ / 免疫抑制

Outline of Research at the Start

マラリアでは、免疫抑制が起こることが知られている。本研究は、マラリア原虫感染のマウスモデルを用いて、免疫抑制に関わる細胞の特性を解析する基礎的な研究である。特に、研究代表者らが発見したサイトカインIL-27を産生する制御性T細胞に焦点を当て、感染経過中の免疫制御におけるTr27細胞と他の細胞との関わり、さらにTr27細胞の認識するマラリア原虫抗原と他のT細胞の認識する抗原の異同を明らかにする。

Outline of Final Research Achievements

We previously reported Plasmodium antigen-specific Tr27 cells that produce regulatory cytokine IL-27 as a novel type of regulatory T cells that are induced in rodent model of malaria. In this study, we investigated the role of Tr27 cells in the regulation of the immune responses during infection, the antigen recognition, and mechanisms underlying their differentiation. We found that the contribution of IL-27 production by Tr27 cells is not as high as that of dendritic cells. We have not been able to determine the Plasmodium antigen recognized by Plasmodium-specific T cells and the molecule that is responsible for the differentiation of Tr27 cells.

Academic Significance and Societal Importance of the Research Achievements

マラリアは毎年２億人以上の感染者と５０万人近くの死者を出す重要な感染症である。しかしながら十分に有効なワクチンは得られていない。マラリアのような慢性感染症では、感染に伴い宿主の免疫応答が修飾・抑制され、十分な免疫防御や免疫記憶が成立しない。従って、マラリアのような慢性感染症を克服するためには、これらの免疫修飾機構を解明することが重要である。
我々の発見したTr27細胞は、感染時に免疫を制御するT細胞であり、マラリアなどの全身性感染症で適度に免疫応答を調整すると考えられる。この細胞に関する理解を深めることは、次世代型の革新的ワクチン開発に重要な情報を提供する。

Research Products

• [Int'l Joint Research] LSHTM(英国)
• [Int'l Joint Research] University of Melbourne(オーストラリア)
• [Int'l Joint Research] メルボルン大学(オーストラリア)
• [Journal Article] Type I interferon production elicits differential CD4+ T-cell responses in mice infected with Plasmodium berghei ANKA and P. chabaudi (2022)
  • Author(s): M Ntita, S-I Inoue, J-Yu Jian, G Bayarsaikhan, K Kimura, D Kimura, M Miyakoda E Nozaki, T Sakurai, D Fernandez-Ruiz, WR. Heath, K Yui.
  • Journal Title: International Immunology Volume: 34 Issue: 1 Pages: 21-33
  • DOI: 10.1093/intimm/dxab090
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection (2021)
  • Author(s): Jian JY, Inoue SI, Bayarsaikhan G, Miyakoda M, Kimura D, Kimura K, Nozaki E, Sakurai T, Fernandez-Ruiz D, Heath WR, Yui K.
  • Journal Title: International Immunology Volume: 33 Issue: 8 Pages: 409-422
  • DOI: 10.1093/intimm/dxab020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species. (2021)
  • Author(s): M H Enders, G Bayarsaikhan, C Huang, S Ghilas, YCheng Chua, R May, A Cozijnsen, V Mollard, G I. McFadden, M H. Lahoud, I Camischi, K Yui, A W. Purcell, RB. Schittenhelm, L Beattie, W R. Heath, D Fernandez-Ruiz.
  • Journal Title: Current Research in Immunology Volume: 2 Pages: 79-92
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Host-pathogen interaction in the tissue environment during Plasmodium blood-stage infection (2021)
  • Author(s): K. Yui, S. Inoue
  • Journal Title: Parasite Immunol Volume: 43 Issue: 2
  • DOI: 10.1111/pim.12763
  • Peer Reviewed
• [Journal Article] Activation and IL-10 production of specific CD4+ T cells are regulated by IL-27 during chronic infection with Plasmodium chabaudi. (2020)
  • Author(s): Sukhbaatar O, Kimura D, Miyakoda M, Nakamae S, Kimura K, Hara H, Yoshida H, Inoue SI, Yui K.
  • Journal Title: Parasitol Int. Volume: 74 Pages: 101994-101994
  • DOI: 10.1016/j.parint.2019.101994
  • NAID: 120006988377
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Inhibitory role of IL-27 in the development of Plasmodium-specific CD4+ T cell memory (2022)
  • Author(s): ML Macalinao, S Inoue, S Tsogtsaikhan, J-Y Jian, G Bayarsaikhan, K Kimura, J Hafalla, H Yoshida, D Kimura, K Yui
  • Organizer: 第14回寄生虫感染免疫研究会
• [Presentation] Role of γδ T cells in antigen specific CD4+ T cell response to Plasmodium chabaudi infection (2022)
  • Author(s): Y Ibraheem, G Bayarsaikhan, ML Macalinao, K Kimura, K Yui, and S-I Inoue
  • Organizer: 第14回寄生虫感染免疫研究会
• [Presentation] IL-27 inhibits the generation and/or maintenance of Plasmodium-specific memory CD4+ T cells during malaria infection (2021)
  • Author(s): Macarinao Maria Lourdes Macapagal, 井上信一、T Sanjaadorj, G Bayarsaikhan, J-Y Jian,木村一美, Hafalla Julius Clemence, D Fernandez-Ruiz, WR. Heath, 吉田裕樹、木村大輔、由井克之
  • Organizer: 第90回日本寄生虫学会
• [Presentation] マラリア原虫感染応答での原虫特異的CD4+T細胞の分化決定におけるγδT 細胞の役割 (2021)
  • Author(s): 井上信一、G Bayarsaikhan、J Jiun-Yua, N Mbaya, T Sanjaadorj, M Macalinao, 木村一美、D Fernandez-Ruiz, WR. Heat、由井克之
  • Organizer: 第90回日本寄生虫学会
• [Presentation] HETEROGENEITY OF MULTIPLEX ANTIMALARIAL ANTIBODY RESPONSES CONFIRM STATUS OF HISTORICAL AND RECENT MALARIA TRANSMISSION IN ENDEMIC AREAS IN THE PHILIPPINES, (2021)
  • Author(s): Maria Lourdes Macalinao, Kimberly Fornace, Tom Hall, Ralph Reyes, Fe Espino, Jennifer Luchavez, Kevin Tetteh, Katsuyuki Yui, Julius Hafalla, Chris Drakeley
  • Organizer: JITMM Virtual 2021
  • Int'l Joint Research
• [Presentation] γδ T cells regulate differentiation of antigen specific CD4+ T cells during malaria (2021)
  • Author(s): Shin-Ichi Inoue、Ganchimeg Bayarsaikhan、 Jiun-Yu Jian、Ntita Mbaya、Sanjaadorj Tsogtsaikhan、Macalinao Malou、Kazumi Kimura、Daniel Fernandez-Ruiz、William Heath、Katsuyuki Yui
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Transient IL-27 blockade enhances CD4+ T cell memory and protection against malaria (2021)
  • Author(s): Maria Lourdes Macalinao, Shin-Ichi Inoue, Sanjaadorj Tsogtsaikhan, Jiun-Yu Jian, Ganchimeg Bayarsaikhan, Kazumi Kimura, Daniel Fernandez-Ruiz, William R. Heath, Julius Hafalla, Hiroki Yoshida, Daisuke Kimura, Katsuyuki Yui
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] CD4+ T cell immune responses and memory during malaria. (2020)
  • Author(s): K. Yui
  • Organizer: The recent advances in Immunology International Conference 2020
  • Int'l Joint Research / Invited
• [Presentation] Differences in memory CD4+ T cells developed after infection with Plasmodium berghei ANKA and Plasmodium chabaudi chabaudi (2019)
  • Author(s): Ntita Mbaya, Shin-Ichi Inoue, Ganchimeg Bayarsaikhan, Jiun-Yu Jian, Kazumi Kimura, Daisuke Kimura, Mana Miyakoda, Daniel Fernandez-Ruiz, R. William Heath, Katsuyuki Yui,
  • Organizer: 第18回あわじ感染と免疫国際フォーラム
  • Int'l Joint Research
• [Presentation] Regulation of T-cell immune responses in malaria: From mice to humans (2019)
  • Author(s): K. Yui
  • Organizer: 019 RITM malaria and parasitic NTDs stakeholder’ forum
  • Int'l Joint Research / Invited
• [Presentation] Two subpopulations of malaria antigen-specific CD4+ T cells during infection with Plasmodium chabaudi (2019)
  • Author(s): J-Y Jian, S-I Inoue, G Bayarsaikhan, M Miyakoda, D Kimura, D Fernandez-Ruiz, WR. Heath, K Yui
  • Organizer: 第48回日本免疫学会
• [Remarks] 長崎大学大学院医歯薬学総合研究科新興感染症病態制御学分野 免疫学分野
  • URL: https://www.med.nagasaki-u.ac.jp/mmi/im/
• [Remarks] 長崎大学大学院医歯薬学総合研究科新興感染症病態制御学系専攻 免疫学分野
  • URL: http://www.med.nagasaki-u.ac.jp/mmi/im/
• [Patent(Industrial Property Rights)] 慢性感染症に対する免疫増強用組成物および慢性感染症治療用医薬 (2022)
  • Inventor(s): 由井克之、井上信一、マリア マカリナオ、吉田裕樹
  • Industrial Property Rights Holder: 由井克之、井上信一、マリア マカリナオ、吉田裕樹
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 慢性感染症に対する免疫増強組成物および慢性感染治療用医薬 (2021)
  • Inventor(s): 由井克之、井上信一、マリア マカリナオ、吉田裕樹
  • Industrial Property Rights Holder: 由井克之、井上信一、マリア マカリナオ、吉田裕樹
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021