Identification of epitopes targeted by TCR-MHC pairs

• Project/Area Number: 18H02430
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43060:System genome science-related
• Research Institution: Osaka University
• Principal Investigator: Standley Daron 大阪大学, 微生物病研究所, 教授 (00448028)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: Immunology / Protein Structure / Protein Function / Disease / Machine Learning / Single cell sequencing / SARS-CoV-2 / CAR T cell / Adaptive immunity / T cell / epitope / machine learning; / structural modeling / adaptive immunity / machine-learning / single cell sequencing / COVID-19 / docking / T cell; / machine learning / immunity / T cell receptor epitope / Biomolecular structure / Machine learning

Outline of Final Research Achievements

Tools for high-throughput structure modeling (Repertoire Builder), clustering (InterClone), TCR-peptide-MHC complex modeling (ImmuneScape) have been developed. These tools are at least as accurate as low-throughput tools, and for Repertoire Builder and InterClone are the only tools in their class. We applied these tools to understand the structural basis of antibodies and TCRs in several diseases, including COVID-19. We experimentally validated identified TCRs-peptide-MHC complexes from SARS-CoV-2.

Academic Significance and Societal Importance of the Research Achievements

免疫システムは、感染症から癌に至るまでさまざまな病気を予防するためにT細胞と抗体を用いる。しかし、T細胞や抗体が、どのようにしてこのような病気に関連するタンパク質を自己由来のタンパク質と区別して認識するのかはまだわかっていない。本計画では、T細胞と抗体の機能を分子レベルで理解するためのソフトウェアを開発した。特に、SARS-CoV-2からT細胞とその標的エピトープを特定することに成功した。これらの結果によって、本計画で開発したソフトウェアの有用性を実証した。

Research Products

• [Int'l Joint Research] Hudson Alpha Inst./Nikolay Dokholyan Penn State Univ./Marco Ruella, Univ.(米国)
• [Int'l Joint Research] MPI-IE(ドイツ)
• [Int'l Joint Research] Curie Inst.(フランス)
• [Journal Article] An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies (2021)
  • Author(s): Liu Yafei +21 +Standley Daron M.、Shioda Tatsuo、Arase Hisashi
  • Journal Title: Cell in press Volume: 1 Pages: 1-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells (2021)
  • Author(s): Nathan Singh + 26+ Daron M Standley +6 + Marco Ruella
  • Journal Title: Nat Med. in press Volume: 1 Pages: 1-1
• [Journal Article] Methods for sequence and structural analysis of B and T cell receptor repertoires (2020)
  • Author(s): Teraguchi Shunsuke、Saputri Dianita S.、Llamas-Covarrubias Mara Anais、Davila Ana、Diez Diego、Nazlica Sedat Aybars、Rozewicki John、Ismanto Hendra S.、Wilamowski Jan、Xie Jiaqi、Xu Zichang、Loza-Lopez Martin de Jesus、van Eerden Floris J.、Li Songling、Standley Daron M.
  • Journal Title: Computational and Structural Biotechnology Journal Volume: 18 Pages: 2000-2011
  • DOI: 10.1016/j.csbj.2020.07.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of Protein Intermolecular Interactions with MAFFT-DASH (2020)
  • Author(s): Rozewicki John、Li Songling、Katoh Kazutaka、Standley Daron M.
  • Journal Title: Multiple Sequence Alignment (Methods in Molecular Biology) Volume: 2232 Pages: 163-177
  • DOI: 10.1007/978-1-0716-1036-7_11
  • ISBN: 9781071610350, 9781071610367
• [Journal Article] Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production (2020)
  • Author(s): Metwally Hozaifa、Tanaka Toshio、Li Songling、Parajuli Gyanu、Kang Sujin、Hanieh Hamza、Hashimoto Shigeru、Chalise Jaya P.、Gemechu Yohannes、Standley Daron M.、Kishimoto Tadamitsu
  • Journal Title: Science Signaling Volume: 13 Issue: 624 Pages: 624-624
  • DOI: 10.1126/scisignal.aay0574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis (2020)
  • Author(s): Fukushima Kiyoharu、Satoh Takashi、Sugihara Fuminori、Sato Yuki、Okamoto Toru、Mitsui Yuichi、Yoshio Sachiyo、Li Songling、Nojima Satoshi、Motooka Daisuke、Nakamura Shota、Kida Hiroshi、Standley Daron M.、Morii Eiichi、Kanto Tatsuya、Yanagita Motoko、Matsuura Yoshiharu、Nagasawa Takashi、Kumanogoh Atsushi、Akira Shizuo
  • Journal Title: Immunity Volume: 52 Issue: 3 Pages: 542-556
  • DOI: 10.1016/j.immuni.2020.02.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Initial phospholipid-dependent Irgb6 targeting to Toxoplasma gondii vacuoles mediates host defense. (2019)
  • Author(s): Lee, Y., Yamada, H., Pradipta, A., Ma, J.S., Okamoto, M., Nagaoka, H., Takashima, E., Standley, D.M., Sasai, M., Takei, K., Yamamoto, M.
  • Journal Title: Life Science Alliance Volume: 3 Issue: 1 Pages: 000-000
  • DOI: 10.26508/lsa.201900549
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reversible control of enantioselectivity by the length of ketone substituent in biocatalytic reduction. (2019)
  • Author(s): Koesoema AA, Sugiyama Y, Sriwong KT, Xu Z, Verina S, Standley DM, Senda M, Senda T, Matsuda T.
  • Journal Title: Applied Microbiology and Biotechnology Volume: 103 Pages: 9529-9541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. (2019)
  • Author(s): Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O.
  • Journal Title: Nat Microbiol Volume: 4 Issue: 9 Pages: 1532-1544
  • DOI: 10.1038/s41564-019-0460-3
  • NAID: 120006731123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis for a highly (S)-enantioselective reductase towards aliphatic ketones with only one carbon difference between side chain. (2019)
  • Author(s): Koesoema AA, Sugiyama Y, Xu Z, Standley DM, Senda M, Senda T, Matsuda T
  • Journal Title: Applied microbiology and biotechnology Volume: 103 Pages: 9543-9553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MAFFT-DASH: integrated protein sequence and structural alignment (2019)
  • Author(s): Rozewicki John、Li Songling、Amada Karlou Mar、Standley Daron M、Katoh Kazutaka
  • Journal Title: Nucleic Acids Research Volume: 47
  • DOI: 10.1093/nar/gkz342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional clustering of B cell receptors using sequence and structural features (2019)
  • Author(s): Xu Zichang、Li Songling、Rozewicki John、Yamashita Kazuo、Teraguchi Shunsuke、Inoue Takeshi、Shinnakasu Ryo、Leach Sarah、Kurosaki Tomohiro、Standley Daron M.
  • Journal Title: Molecular Systems Design & Engineering Volume: 4 Issue: 4 Pages: 769-778
  • DOI: 10.1039/c9me00021f
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repertoire Builder: high-throughput structural modeling of B and T cell receptors (2019)
  • Author(s): Schritt Dimitri、Li Songling、Rozewicki John、Katoh Kazutaka、Yamashita Kazuo、Volkmuth Wayne、Cavet Guy、Standley Daron M.
  • Journal Title: Molecular Systems Design & Engineering Volume: 4 Issue: 4 Pages: 761-768
  • DOI: 10.1039/c9me00020h
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translation-dependent unwinding of stem?loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs (2019)
  • Author(s): Mino Takashi、Iwai Noriki、Endo Masayuki、Inoue Kentaro、Akaki Kotaro、Hia Fabian、Uehata Takuya、Emura Tomoko、Hidaka Kumi、Suzuki Yutaka、Standley Daron M、Okada-Hatakeyama Mariko、Ohno Shigeo、Sugiyama Hiroshi、Yamashita Akio、Takeuchi Osamu
  • Journal Title: Nucleic Acids Research Volume: 47 Pages: 8838-8859
  • DOI: 10.1093/nar/gkz628
  • NAID: 120006708220
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association (2019)
  • Author(s): Fukuda Hirofumi、Li Songling、Sardo Luca、Smith Jessica L.、Yamashita Kazuo、Sarca Anamaria D.、Shirakawa Kotaro、Standley Daron M.、Takaori-Kondo Akifumi、Izumi Taisuke
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 9 Pages: 1-13
  • DOI: 10.3389/fcimb.2019.00129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis. (2019)
  • Author(s): Takeda K, Sakakibara S, Yamashita K, Motooka D, Nakamura S, El Hussien MA, Katayama J, Maeda Y, Nakata M, Hamada S, Standley DM, Hayama M, Shikina T, Inohara H, Kikutani H.
  • Journal Title: J Allergy Clin Immunol Volume: 143 Issue: 3 Pages: 1163-1175
  • DOI: 10.1016/j.jaci.2018.07.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural modeling of lymphocyte receptors and their antigens. (2019)
  • Author(s): Li S, Wilamowski J, Teraguchi S, Van Eerden F, Rozewiki J, Davila A, Xu Z, Katoh K, Standley DM,
  • Journal Title: Meth Mol Biol Volume: in press
  • Peer Reviewed
• [Journal Article] Repertoire Builder: High-throughput structural modeling of B and T cell receptors Mol. (2019)
  • Author(s): D. Schritt, S. Li, J. Rozewicki, K. Katoh, K. Yamashita, W. Volkmuth, G. Cavet and D. Standley,
  • Journal Title: Syst. Des. Eng Volume: in press
  • Peer Reviewed
• [Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. (2019)
  • Author(s): Yamasoba, D. et al.
  • Journal Title: Nat. Microbiol. Volume: in press
  • Peer Reviewed
• [Journal Article] MAFFT-DASH: integrated protein sequence and structural alignment. (2019)
  • Author(s): Rozewicki, J., Li, S., K., A., Standley, D. M. & Kazutaka, K.
  • Journal Title: Nucleic Acids Res. Volume: in press
  • Peer Reviewed
• [Journal Article] Arid5a stabilizes OX40 mRNA in murine CD4+ T cells by recognizing a stem-loop structure in its 3′UTR (2018)
  • Author(s): Hanieh Hamza、Masuda Kazuya、Metwally Hozaifa、Chalise Jaya P.、Mohamed Maged、Nyati Kishan K.、Standley Daron M.、Li Songling、Higa Mitsuru、Zaman Mohammad M.、Kishimoto Tadamitsu
  • Journal Title: European Journal of Immunology Volume: 48 Issue: 4 Pages: 593-604
  • DOI: 10.1002/eji.201747109
  • Peer Reviewed
• [Presentation] "Toward high-throughput antibody-antigen modeling" (2020)
  • Author(s): Daron Standley
  • Organizer: Kobe Univ. (The Basis for Computational Life Science 7)
  • Invited
• [Presentation] Modeling the structure and function of lymphocyte receptors from their sequences (2019)
  • Author(s): Daron Standley
  • Organizer: Immunogenomics 2019
  • Int'l Joint Research / Invited
• [Presentation] High-throughput modeling of lymphocyte receptors and their antigens (2018)
  • Author(s): Daron Standley
  • Organizer: Hot Spring Harbor International Symposium
  • Int'l Joint Research
• [Book] In Vitro Differentiation of T-Cells (2019)
  • Author(s): DARON M. STANDLEY 加藤 和貴 LI SONGLING VAN EERDEN FLORIS JAN ROZEWICKI JOHN JAMES WILAMOWSKI JAN DAVILA ANA XU ZICHANG
  • Publisher: Humana Press