Identification of cardiac APCs that activate NKT cells and induce anti-inflammatory function after alpha-GalCer infusion

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K08791
• Research Institution: Kitasato University
• Principal Investigator: 岩渕 和也 北里大学, 医学部, 教授 (20184898)
• Co-Investigator(Kenkyū-buntansha): 佐藤 雅 北里大学, 医学部, 講師 (40611843)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: NKT細胞 / CD1d / 抗原提示細胞 / 実験的自己免疫性心筋炎 / 抗炎症作用 / NKT細胞リガンド / 疾患モデル / マクロファージ

Outline of Annual Research Achievements

これまで、実験的自己免疫性心筋炎（EAMC）の誘導にはマウス心筋ミオシン重鎖αアイソフォームの614-629番残基ペプチド（Ac-SLKLMATLFSTYASAD; N端のセリンはアセチル化）（MyHCα614-629）と完全フロイントアジュバント（CFA）との1:1（v/v）エマルジョンを作製、BALB/cマウスに皮下注射、百日咳毒素を追加アジュバントして腹腔内投与し、７日後にエマルジョンのみ追加免疫という標準的方法を使用してきた。しかし、ペプチドの水溶性に問題があるためEAMCの誘導率が悪く、実験治療の奏功性の判定に苦労することが少なくなかった。本年度のAnzaiらの論文（J Exp Med 216: 369-83, 2019）で、抗原ペプチドコアとしては同じであるが、両端にアルギニンを付加したMyHCαR614-629Rを用いていることを知った。そこで同じペプチドを合成し、試行したところ、水溶性・誘導率が向上することがわかり、以降このペプチドを用いて実験を行った。前年度の結果である感作時のiNKT細胞活性化がEAMC軽症化に寄与する結果を受けて、iNKT細胞欠損のTRAJ18-/-マウス（東大医科研・現金沢大医の渡会博士より供与）にEAMCを誘導した。その結果、野生型のBALB/cに比較して、TRAJ18-/-マウスで炎症は重症化し（クレアチンキナーゼ・トロポニンIなどの心筋破壊指標が高値）、単核細胞浸潤・線維化病巣面積は有意に増大した。これは野性型マウスではNKT細胞リガンドであるα-GCを投与したマウスにおいてTNF-α-低下とIL-10増加を伴って、心筋への浸潤細胞・線維化病巣の減少が観察されたことと併せ、iNKT細胞の存在や免疫時におけるiNKT細胞の活性化がEAMCの軽症化に寄与することを示していると考えられた。

Research Products

• [Int'l Joint Research] Vanderbilt University School of Medicine(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Vanderbilt University School of Medicine
• [Journal Article] Amelioration of experimental autoimmune myocarditis through activation of Invariant natural killer T cells by administration of a-galactosylceramide (2020)
  • Author(s): Yoshino K, Satoh M, Iwayama T, Kobayashi S, Okamoto H, Eshima K, Watarai H, Iwabuchi K
  • Journal Title: Kitasato Medical Journal Volume: 50 Pages: 60-72
  • Peer Reviewed
• [Journal Article] De novo generation of CD1d1-deficient NKT-cell hybridomas from CD1d-/- mice or by gene editing of CD1d+ hybridomas (2020)
  • Author(s): Satoh M, Saeki M, Yoshino K, Mita K, Iizuka M, Hattori A, Takeuchi E, Eshima K, Iwabuchi K.
  • Journal Title: Kitasato Medical Journal Volume: 50 Pages: 34-43
  • Peer Reviewed
• [Journal Article] NF-κB-inducing kinase contributes to normal development of cortical thymic epithelial cells: its possible role in shaping a proper T-cell repertoire. (2020)
  • Author(s): Eshima K, Misawa K, Ohashi C, Noma H, Iwabuchi K.
  • Journal Title: Immunology Volume: - Pages: -
  • DOI: 10.1111/imm.13186
  • Peer Reviewed / Open Access
• [Journal Article] Attenuation of experimental autoimmune uveoretinitis in mice by IKKβ inhibitor IMD-0354. (2020)
  • Author(s): Liu Y, Kitaichi N, Wu D, Hase K, Satoh M, Iwata D, Namba K, Kanda A, Noda K, Itai A, Iwabuchi K, Ishida S.
  • Journal Title: Biochem Biophys Res Commun Volume: 525 Pages: 589-594
  • DOI: 10.1016/j.bbrc.2020.02.117.
  • Peer Reviewed / Open Access
• [Journal Article] The disruption of invariant natural killer T cells exacerbates cardiac hypertrophy and failure caused by pressure overload in mice. (2020)
  • Author(s): Takahashi M, Kinugawa S, Takada S, Kakutani N, Furihata T, Sobirin MA, Fukushima A, Obata Y, Saito A, Ishimori N, Iwabuchi K, Tsutsui H.
  • Journal Title: Exp Physiol Volume: 105 Pages: 489-501
  • DOI: 10.1113/EP087652.
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Role of CD1- and MR1-Restricted T Cells in Immunity and Disease. (2020)
  • Author(s): Iwabuchi K, Van Kaer L.
  • Journal Title: Front Immunol Volume: - Pages: -
  • DOI: 10.3389/fimmu.2019.01837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of NKT cell-macrophageinteraction in obesity (2019)
  • Author(s): Satoh M, Iwabuchi K
  • Organizer: EMBO Workshop CD1-MR1 2019
  • Int'l Joint Research
• [Presentation] An overview of innate lymphocytes: unconventional T cells and innate lymphoid cells (2019)
  • Author(s): Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
  • Invited
• [Presentation] The interaction of NKT cell and macrophage has regulatory function in obesity (2019)
  • Author(s): Satoh M, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] Potential role of invariant NKT cells in experimental autoimmune myocarditis in mice (2019)
  • Author(s): Yoshino K, Satoh M, Watarai H, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] Relapse of experimental autoimmune uveoretinitis (EAU) with super antigen is ameliorated by concomitant NKT-cell activation (2019)
  • Author(s): Tajiri N, Satoh M, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] The alteration of NKT-cell function in mice fed on high fat diet (2019)
  • Author(s): Hane K, Satoh M, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] MR1/MAIT cell alleviates allergic contact dermatitis through reduction of IL-17 production (2019)
  • Author(s): Imahashi N, Satoh M, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] Role of T-box transcription factor Eomesodermin, in Perforin/Granzyme exocytosis pathway of cytolysis by CD8+ CTLs (2019)
  • Author(s): Morikawa Y, Eshima K, Murakami M, Kondou H, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] The Roles of Eomesodermin in T cell exhaustion (2019)
  • Author(s): Murakami M, Eshima K, Iwabuchi K
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
• [Presentation] T細胞疲弊化におけるT-boxファミリー転写因子Eomesoderminの役割の解析 (2019)
  • Author(s): 江島耕二、村上南、森川優樹、岩渕和也
  • Organizer: 京都Tセルカンファレンス（KTCC）
• [Book] Role of CD1- and MR1-restricted T cells in Immunity and Disease (2019)
  • Author(s): Iwabuchi K, Van Kaer L eds.
  • Total Pages: 427
  • Publisher: Frontiers Media (Lausanne)
  • ISBN: 978-2-88963-122-3
• [Remarks] 北里大学医学部免疫学・大学院医療系研究科細胞免疫学
  • URL: http://www.med.kitasato-u.ac.jp/immunology/