Immune regulation by sensing endogenous lipid composition changes via inhibitory C-type lectin receptor

• Project/Area Number: 19K07623
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kumamoto University
• Principal Investigator: Motozono Chihiro 熊本大学, ヒトレトロウイルス学共同研究センター, 講師 (10642910)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 免疫受容体 / 抑制型受容体 / 結核菌 / 脂質

Outline of Research at the Start

本研究は、抑制型免疫受容体が生体の異常に伴って変化する内因性脂質をリガンドとして感知し、免疫応答の抑制化に関わっているか否か明らかにすることで、抑制型免疫受容体が担う生体の恒常性維持機構の一端の解明を目指す。本研究成果は、生体適合性が高い内因性脂質含有アジュバントを用いた免疫応答制御法、ならびに、抑制型免疫受容体に対する抗体投与もしくはアンタゴニスト化合物の開発により、免疫抑制機構の解除を標的とした新たな免疫チェックポイント阻害剤の開発に寄与すると期待される。

Outline of Final Research Achievements

Although the activating signals are balanced by inhibitory receptor-mediated signals, which maintains immune homeostasis, ligand recognitions and functions via inhibitory innate-receptors bearing ITIMs (Immunoreceptor tyrosine-based inhibitory motifs) remains unclear. To identify their endogenous ligands, we employed nuclear factor of activated T-cells (NFAT)-GFP reporter cells expressing chimeric inhibitory CLRs fused to CD3ζ and analyzed the reporter activity in response to various components. We identified the structure of their lipid ligands from plasma membrane and Mycobacteria. Mycobacteria infection experiment revealed that T cell recall responses were substantially enhanced in mice lacking the inhibitory receptor. These data indicate that blockade of the inhibitory receptor interaction and signaling potentiate cellular immunity against mycobacteria.

Academic Significance and Societal Importance of the Research Achievements

免疫応答は活性化シグナルとそれを制御する抑制性シグナルとの正負のバランスによって適切に調節されているが、抑制化シグナルを担っている抑制型免疫受容体の機能は未だ不明な点が多い。本研究では、抑制型受容体の内因性脂質リガンドならびに結核菌由来の脂質リガンド構造の同定に成功した。また結核菌感染動物モデルにおいて、野生型と比較して抑制型受容体欠損マウスでT細胞応答が増強されることが明らかになった。以上から、この抑制型受容体の認識を阻害することで免疫応答を増強させる新たな免疫チェックポイント阻害剤の可能性が示唆された。

Research Products

• [Int'l Joint Research] Weizmann Institute of Science(イスラエル)
• [Int'l Joint Research] Victoria University of Wellington(ニュージーランド)
• [Journal Article] The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance (2022)
  • Author(s): Kimura Izumi、Kosugi Yusuke、Wu Jiaqi、other 17 authors、Saito Akatsuki、Nakagawa So、Sato Kei
  • Journal Title: Cell Reports Volume: 38 Issue: 2 Pages: 110218-110218
  • DOI: 10.1016/j.celrep.2021.110218
  • NAID: 120007183813
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Resistance of SARS-CoV-2 variants to neutralization by antibodies induced in convalescent patients with COVID-19 (2021)
  • Author(s): Kaku Y, Kuwata T, Zahid HM, Hashiguchi T, Noda T, Kuramoto N, Biswas S, Matsumoto K, Shimizu M, Kawanami Y, Shimura K, Onishi C, Muramoto Y, Suzuki T, Sasaki J, Nagasaki Y, Minami R, Motozono C, Toyoda M, Takahashi H, Kishi H, Fujii K, Tatsuke T, Ikeda T, Maeda Y, Ueno T, Koyanagi Y, Iwagoe H, Matsushita S.
  • Journal Title: Cell Reports Volume: 36 Issue: 2 Pages: 109385-109385
  • DOI: 10.1016/j.celrep.2021.109385
  • Peer Reviewed / Open Access
• [Journal Article] SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity (2021)
  • Author(s): Motozono Chihiro、Toyoda Mako、Zahradnik Jiri、Saito Akatsuki、Other 19 authors、Ikeda Terumasa、Nakagawa So、Ueno Takamasa、Sato Kei
  • Journal Title: Cell Host & Microbe Volume: 29 Issue: 7 Pages: 1124-1136
  • DOI: 10.1016/j.chom.2021.06.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trehalose diamide glycolipids augment antigen-specific antibody responses in a Mincle-dependent manner. (2021)
  • Author(s): Lynch, AT., Motozono, C., Foster, AJ., Kodar, K., Dangerfield, EM., Yamasaki, S., Wedlock, DN., Timmer, MSM., Stocker, BL.
  • Journal Title: Bioorg Chem. Volume: 110 Pages: 104747-104747
  • DOI: 10.1016/j.bioorg.2021.104747
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The effects of 5‐OP‐RU stereochemistry on its stability and MAIT‐MR1 axis (2020)
  • Author(s): Matsuoka Takuro、Motozono Chihiro、Hattori Akira、Kakeya Hideaki、Yamasaki Sho、Oishi Shinya、Ohno Hiroaki、Inuki Shinsuke
  • Journal Title: ChemBioChem Volume: 22 Issue: 4 Pages: 672-678
  • DOI: 10.1002/cbic.202000466
  • Peer Reviewed
• [Journal Article] Agonistic or antagonistic mucosal-associated invariant T (MAIT) cell activity is determined by the 6-alkylamino substituent on uracil MR1 ligands (2020)
  • Author(s): Braganza Chriselle D.、Motozono Chihiro、Sonoda Koh-Hei、Yamasaki Sho、Shibata Kensuke、Timmer Mattie S. M.、Stocker Bridget L.
  • Journal Title: Chemical Communications Volume: in press Issue: 39 Pages: 529-5294
  • DOI: 10.1039/d0cc00247j
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo delivery of an exogenous molecule into murine T lymphocytes using a lymphatic drug delivery system combined with sonoporation. (2020)
  • Author(s): Kato S, Shirai Y, Motozono C, Kanzaki H, Mori S, Kodama T
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 4 Pages: 1025-1031
  • DOI: 10.1016/j.bbrc.2020.02.174
  • Peer Reviewed / Open Access
• [Journal Article] Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung. (2019)
  • Author(s): Takamura, S., Kato, S., Motozono, C., Shimaoka, T., Ueha, S., Matsuo, K., Miyauchi, K., Masumoto, T., Katsushima, A., Nakayama, T., Tomura, M., Matsushima, K., Kubo, M. & Miyazawa, M.
  • Journal Title: J Exp Med. Volume: 216 Issue: 12 Pages: 2736-2747
  • DOI: 10.1084/jem.20190557
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effect of MR1 ligand glycol-analogues on mucosal-associated invariant T (MAIT) cell activation. (2019)
  • Author(s): Braganza, CD., Shibata, K., Fujiwara, A., Motozono, C., Sonoda, KH., Yamasaki, S., Stocker, BL., Timmer, MSM.
  • Journal Title: Org Biomol Chem. Volume: 17 Issue: 40 Pages: 8992-9000
  • DOI: 10.1039/c9ob01436e
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCRαβ+CD8αα+ T cells. (2019)
  • Author(s): Ishifune C, Tsukumo S, Maekawa Y, Hozumi K, Chung D, Motozono C, Yamasaki S, Nakano H, Yasutomo K.
  • Journal Title: PLoS Biology Volume: - Issue: 5 Pages: e3000262-e3000262
  • DOI: 10.1371/journal.pbio.3000262
  • NAID: 120006812006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] SARS-CoV-2 spike L452R and Y453F variants confer escape from immunodominant HLA-A24-restricted T cell recognition (2021)
  • Author(s): Motozono C, Hamana H, Udaka K, Kishi H, Ueno T
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 新型コロナウイルス L452R変異はHLA-A24拘束性T細胞の認識から逃避する (2021)
  • Author(s): 本園千尋、浜名洋、Isaac Ngare、豊田真子、Toong Seng Ta、宇高恵子、岸裕幸、佐藤佳、上野貴将
  • Organizer: 第68回 日本ウイルス学会学術集会
• [Presentation] フローサイトメトリーを基盤とした新型コロナウイルス特異的T細胞の検出と機能解析 (2021)
  • Author(s): 本園千尋，Isaac Ngare，上野貴将
  • Organizer: 第31回日本サイトメトリー学会学術集会
• [Presentation] 抑制型免疫受容体が内因性脂質変化を感知して誘導する免疫応答制御 (2020)
  • Author(s): 本園 千尋、鳥越 祥太、西村 直矢、森田 真也、宮本 智文、山﨑 晶
  • Organizer: 第36回 日本DDS会学術集会
  • Invited
• [Presentation] Capturing and identification of MR1-binding molecules using unfolded MR1 protein. (2019)
  • Author(s): C. Motozono, HS. Ismanto, K. Shibata, and S. Yamasaki.
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology, December 11-13, 2019, Shizuoka, Japan
• [Remarks] 熊本大学ヒトレトロウイルス学共同研究センター感染免疫学分野
  • URL: https://caids-kumamoto-u.wixsite.com/ueno-lab
• [Remarks] 熊本大学ヒトレトロウイルス学共同研究センター予防開発部門感染免疫学分野
  • URL: https://caids-kumamoto-u.wixsite.com/ueno-lab
• [Remarks] 大阪大学微生物病研究所分子免疫制御分野
  • URL: http://molimm.biken.osaka-u.ac.jp