Elucidating molecular mechanisms of the regulation of immunodominance

• Project/Area Number: 19H03423
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Okazaki Il-mi 東京大学, 定量生命科学研究所, 准教授 (50452339)
• 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: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 免疫ドミナンス / LAG-3 / 免疫偏向性

Outline of Research at the Start

細菌やウイルスなどの微生物には多くのタンパク質が含まれ、各々のタンパク質についてT細胞が応答し得るエピトープが多数存在する。しかし実際には、それらの中で特定のエピトープに対してT細胞応答が優位に働くことが知られており、免疫偏向性と呼ばれる。実際にT細胞がどのエピトープを標的とするかという疑問は、獲得免疫システムにおいて最も原理的な命題の一つと言えるが、免疫偏向性がどのように決まっているかについては、多くの謎に包まれている。本研究課題では、抑制性免疫補助受容体の一つであるLAG-3に着目して免疫偏向性が生じるメカニズムおよび免疫偏向性の生物学的意義を明らかにする。

Outline of Final Research Achievements

We analyzed the possible involvement of an inhibitory co-receptor LAG-3 in the regulation of T cell immunodominance and revealed that LAG-3 selectively suppresses T cell responses towards dominant epitopes among many of immunogenic peptides, suggesting that LAG-3 mitigates immunodominance to ensure diversity of immune responses. We identified amino acid substitutions within the epitopes that affect binding to LAG-3. We also clarified LAG-3 sensitivity of T cells that express TCRs recognizing these epitopes with amino acid substitutions.

Academic Significance and Societal Importance of the Research Achievements

免疫偏向性がどのように決定されるかについては多くの謎に包まれているが、ペプチド／MHCクラスIIとLAG-3の結合が免疫偏向性に与える影響を明らかにした。免疫応答の指向性が決定されるメカニズムが解明されれば、免疫応答を自在に操ることがより現実的となる。特に、がんや感染症に対するワクチン療法について、より効果的なワクチンのデザインが可能になると期待される。

Research Products

• [Journal Article] Binding of LAG-3 to stable peptide-MHC class II limits T?cell function and suppresses autoimmunity and anti-cancer immunity (2022)
  • Author(s): Maruhashi Takumi、Sugiura Daisuke、Okazaki Il-mi、Shimizu Kenji、Maeda Takeo K.、Ikubo Jun、Yoshikawa Harunori、Maenaka Katsumi、Ishimaru Naozumi、Kosako Hidetaka、Takemoto Tatsuya、Okazaki Taku
  • Journal Title: Immunity Volume: - Issue: 5 Pages: 912-924
  • DOI: 10.1016/j.immuni.2022.03.013
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity (2022)
  • Author(s): Sugiura Daisuke、Okazaki Il-mi、Maeda Takeo K.、Maruhashi Takumi、Shimizu Kenji、Arakaki Rieko、Takemoto Tatsuya、Ishimaru Naozumi、Okazaki Taku
  • Journal Title: Nature Immunology Volume: 23 Issue: 3 Pages: 399-410
  • DOI: 10.1038/s41590-021-01125-7
  • Peer Reviewed / Open Access
• [Journal Article] T-cell-intrinsic and -extrinsic regulation of PD-1 function (2021)
  • Author(s): Sugiura Daisuke、Shimizu Kenji、Maruhashi Takumi、Okazaki Il-mi、Okazaki Taku
  • Journal Title: International Immunology Volume: 33 Issue: 12 Pages: 693-698
  • DOI: 10.1093/intimm/dxab077
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 preferentially inhibits the activation of low-affinity T cells (2021)
  • Author(s): Shimizu Kenji、Sugiura Daisuke、Okazaki Il-mi、Maruhashi Takumi、Takemoto Tatsuya、Okazaki Taku
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 35
  • DOI: 10.1073/pnas.2107141118
  • Peer Reviewed / Open Access
• [Journal Article] LAG-3: from molecular functions to clinical applications (2020)
  • Author(s): Maruhashi Takumi、Sugiura Daisuke、Okazaki Il-mi、Okazaki Taku
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 8 Issue: 2 Pages: e001014-e001014
  • DOI: 10.1136/jitc-2020-001014
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation (2020)
  • Author(s): Shimizu Kenji、Sugiura Daisuke、Okazaki Il-mi、Maruhashi Takumi、Takegami Yujiro、Cheng Chaoyang、Ozaki Soichi、Okazaki Taku
  • Journal Title: Molecular Cell Volume: 77 Issue: 5 Pages: 937-950
  • DOI: 10.1016/j.molcel.2019.12.012
  • Peer Reviewed
• [Journal Article] Stimulatory and Inhibitory Co-signals in Autoimmunity (2019)
  • Author(s): Okazaki Taku、Okazaki Il-mi
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 1189 Pages: 213-232
  • DOI: 10.1007/978-981-32-9717-3_8
  • ISBN: 9789813297166, 9789813297173
  • Peer Reviewed
• [Journal Article] Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells (2019)
  • Author(s): Maeda Natsumi、Maruhashi Takumi、Sugiura Daisuke、Shimizu Kenji、Okazaki Il-mi、Okazaki Taku
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 52 Pages: 19896-19906
  • DOI: 10.1074/jbc.ra119.010379
  • Peer Reviewed
• [Journal Article] PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions (2019)
  • Author(s): Okamura Hikari、Okazaki Il-mi、Shimizu Kenji、Maruhashi Takumi、Sugiura Daisuke、Mizuno Reina、Okazaki Taku
  • Journal Title: Journal of Autoimmunity Volume: 105 Pages: 102296-102296
  • DOI: 10.1016/j.jaut.2019.06.007
  • Peer Reviewed / Open Access
• [Journal Article] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses (2019)
  • Author(s): Sugiura Daisuke、Maruhashi Takumi、Okazaki Il-mi、Shimizu Kenji、Maeda Takeo K.、Takemoto Tatsuya、Okazaki Taku
  • Journal Title: Science Volume: 364 Issue: 6440 Pages: 558-566
  • DOI: 10.1126/science.aav7062
  • Peer Reviewed
• [Presentation] Regulatory mechanisms of T cell activation by immuno-inhibitory co-receptors. (2021)
  • Author(s): Taku Okazaki, Kenji Shimizu, Takumi Maruhashi, Daisuke Sugiura, Il-mi Okazaki
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] LAG-3 engagement with stable pMHCII is essential for the exertion of its inhibitory function. (2021)
  • Author(s): Takumi Maruhashi, Daisuke Sugiura, Il-mi Okazaki, Kenji Shimizu, Taku Okazaki
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] PD-1 elicitation by the dissociation of cis-PD-L1/CD80 duplex inhibits T cell activation and alleviates autoimmunity. (2021)
  • Author(s): Daisuke Sugiura, Il-mi Okazaki, Takumi Maruhashi, Kenji Shimizu, Reiko Arakaki, Naozumi Ishimaru, Taku Okazaki
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] PD-1 preferentially inhibits the activation of low affinity T cells. (2021)
  • Author(s): Kenji Shimizu, Daisuke Sugiura, Il-mi Okazaki, Takumi Maruhashi, Taku Okazaki
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Regulatory mechanisms of T cell activation by immuno-inhibitory co-receptors (2021)
  • Author(s): Taku Okazaki, Daisuke Sugiura, Takumi Maruhashi, Kenji Shimizu, Il-mi Okazaki
  • Organizer: FIMSA2021, Federation of Immunological Societies of Asia-Oceania
• [Presentation] シスPD-L1/CD80結合がT細胞活性化段階におけるPD-1の抑制機能を制限する (2020)
  • Author(s): 杉浦大祐, 丸橋拓海, 岡崎一美, 清水謙次, 岡崎 拓
  • Organizer: 第7回JCRベーシックリサーチカンファレンス
  • Invited
• [Presentation] Regulatory mechanisms of T cell activation by immuno-inhibitory co-receptors. (2020)
  • Author(s): Taku Okazaki, Kenji Shimizu, Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] Restriction of PD-1 function for optimal T cell activation (2019)
  • Author(s): Okazaki T, Sugiura D, Maruhashi T, Shimizu K, Okazaki IM
  • Organizer: 2019 International Symposium of Korean Autoimmunity - Synovitis Study Group
  • Int'l Joint Research / Invited
• [Presentation] Restriction of PD-1 function for optimal T cell responses (2019)
  • Author(s): Okazaki T, Sugiura D, Maruhashi T, Shimizu K, Okazaki IM
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
  • Invited
• [Presentation] Binding properties between LAG-3 and two potential ligands, stable pMHCII and FGL1 (2019)
  • Author(s): Maruhashi T, Ikubo J, Sugiura D, Okazaki IM, Okazaki T
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses (2019)
  • Author(s): Sugiura D, Maruhashi T, Shimizu K, Okazaki IM, Okazaki T
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] PD-1 imposes qualitative control of cellular transcriptomes in response to T cell activation (2019)
  • Author(s): Shimizu K, Sugiura D, Okazaki IM, Maruhashi T, Takegami Y, Cheng C, Ozaki S, Okazaki T
  • Organizer: The 42nd Annual Meeting of the Molecular Biology Society of Japan
• [Presentation] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses (2019)
  • Author(s): Okazaki T, Sugiura D, Maruhashi T, Shimizu K, Okazaki IM
  • Organizer: 7th Annual Meeting of the International Cytokine and Interferon Society (Cytokines 2019)
  • Int'l Joint Research / Invited
• [Presentation] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses (2019)
  • Author(s): Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, Okazaki T
  • Organizer: The 14th International Symposium of the Institute Network for Biomedical Sciences
  • Int'l Joint Research
• [Presentation] LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII (2019)
  • Author(s): Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, Okazaki T
  • Organizer: The 14th International Symposium of the Institute Network for Biomedical Sciences
  • Int'l Joint Research
• [Presentation] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses (2019)
  • Author(s): Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, Okazaki T
  • Organizer: The RIKEN-IMS International Symposium on Immunology 2019
  • Int'l Joint Research / Invited
• [Presentation] 抑制性免疫補助受容体PD-1の機能制御機構 (2019)
  • Author(s): 岡崎 拓, 杉浦大祐, 丸橋拓海, 清水謙次, 岡崎一美
  • Organizer: The 92nd Annual Meeting of the Japanese Biochemical Society
  • Invited
• [Presentation] 抑制性免疫補助受容体によるがん免疫と自己免疫の制御 (2019)
  • Author(s): 岡崎 拓, 丸橋拓海, 杉浦大祐, 清水謙次, 岡崎一美
  • Organizer: The 23rd Annual Meeting of Japanese Association of Cancer Immunology
  • Invited
• [Presentation] シンギュラリティ生物学による自己免疫疾患制御機構の解明 (2019)
  • Author(s): 岡崎 拓, 岡村陽香里, 清水謙次, 丸橋拓海, 杉浦大祐, 岡崎一美
  • Organizer: Joint Annual Meeting of the 71st Japan Society for Cell Biology and the 19th Protein Science Society of Japan
  • Invited
• [Presentation] シスPD-L1/CD80結合がT細胞活性化段階におけるPD-1の抑制機能を制限する (2019)
  • Author(s): 杉浦大祐, 丸橋拓海, 岡崎一美, 清水謙次, 竹本龍也, 岡崎 拓
  • Organizer: 第18回四国免疫フォーラム
• [Presentation] T細胞の抗原刺激による遺伝子発現変動にPD-1が与える影響の網羅的解析 (2019)
  • Author(s): 清水謙次, 杉浦大祐, 岡崎一美, 丸橋拓海, 岡崎 拓
  • Organizer: 第18回四国免疫フォーラム
• [Remarks] 東京大学定量生命科学研究所分子免疫学分野ホームページ
  • URL: http://www.iqb.u-tokyo.ac.jp/okazakilab/
• [Remarks] がん免疫療法の標的分子LAG-3が抑制機能を発揮するメカニズムを解明
  • URL: https://www.u-tokyo.ac.jp/focus/ja/press/z0207_00058.html
• [Remarks] 自己免疫疾患に対する新規治療法を発見
  • URL: https://www.u-tokyo.ac.jp/focus/ja/press/z0207_00057.html
• [Remarks] PD-1は抗原親和性の弱いT細胞を選択的に抑制する
  • URL: https://www.u-tokyo.ac.jp/focus/ja/press/z0207_00048.html
• [Remarks] 東京大学定量生命科学研究所分子免疫学研究分野ホームページ
  • URL: http://www.iam.u-tokyo.ac.jp/okazakilab/