Paradigm shift in antigen recognition of T cells

• Project/Area Number: 18K19441
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: University of Toyama
• Principal Investigator: Kishi Hiroyuki 富山大学, 学術研究部医学系, 教授 (60186210)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: T細胞受容体 / 抗原認識 / シス相互作用 / cis相互作用 / 抗原/MHC複合体 / MHC/ペプチド複合体

Outline of Final Research Achievements

Macrophages that phagocytose pathogenic microorganisms, or virus-infected cells degrade bacterial or viral proteins into peptides and present them on the cell surface by binding them onto the major histocompatibility complex (MHC) molecules on the cells. T cells use the T cell receptors (TCR) to recognize MHC molecule/peptide complexes on the target cells and eliminate viruses and bacteria from the body. In this context, the TCR interacts with MHC molecule/peptide complexes on the surface of different cells. In this study, we showed that antigenic protein-derived peptides expressed in T cells is presented to the MHC molecules on the T cells, interacts with the same cell surface TCR (cis-interaction), and activates the T cells. Furthermore, the application of cis-interaction of TCR and MHC/peptide complexes was investigated.

Academic Significance and Societal Importance of the Research Achievements

従来、T細胞は、TCRを用いて、標的細胞上のMHC分子／ペプチド複合体を認識することが知られていた(trans相互作用)。本研究により、T細胞上のTCRが自分自身のMHC分子／ペプチド複合体とcisの相互作用をすることで活性化しうることが示されたことで、今後、T細胞の活性化を考える際に、transの相互作用に加えてcisの相互作用の可能性も同時に考える必要がある。また、cisの相互作用を用いた抗原同定法や抗原特異的T細胞の同定法によりT細胞の解析がより進展すると期待される。

Research Products

• [Journal Article] Non-transmissible MV Vector with Segmented RNA Genome Establishes Different Types of iPSCs from Hematopoietic Cells (2020)
  • Author(s): Hiramoto T、Tahara M、Liao J、Soda Y、Miura Y、Kurita R、Hamana H、Inoue K、Kohara H、Miyamoto S、Hijikata Y、Okano S、Yamaguchi Y、Oda Y、Ichiyanagi K、Toh H、Sasaki H、Kishi H、Ryo A、Muraguchi A、Takeda M、Tani K
  • Journal Title: Molecular Therapy Volume: 28 Issue: 1 Pages: 129-141
  • DOI: 10.1016/j.ymthe.2019.09.007
  • Peer Reviewed / Open Access
• [Journal Article] A novel and simple method to produce large amounts of recombinant soluble peptide/major histocompatibility complex monomers for analysis of antigen-specific human T cell receptors (2019)
  • Author(s): Lyu Fulian、Ozawa Tatsuhiko、Hamana Hiroshi、Kobayashi Eiji、Muraguchi Atsushi、Kishi Hiroyuki
  • Journal Title: New Biotechnology Volume: 49 Pages: 169-177
  • DOI: 10.1016/j.nbt.2018.11.005
  • Peer Reviewed
• [Journal Article] Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations (2019)
  • Author(s): Iiizumi Susumu、Ohtake Junya、Murakami Naoko、Kouro Taku、Kawahara Mamoru、Isoda Fumiko、Hamana Hiroshi、Kishi Hiroyuki、Nakamura Norihiro、Sasada Tetsuro
  • Journal Title: Cancers Volume: 11 Issue: 2 Pages: 266-266
  • DOI: 10.3390/cancers11020266
  • Peer Reviewed / Open Access
• [Journal Article] Isolation of Antigen-Specific, Antibody-Secreting Cells Using a Chip-Based Immunospot Array (2018)
  • Author(s): Kishi Hiroyuki、Ozawa Tatsuhiko、Hamana Hiroshi、Kobayashi Eiji、Muraguchi Atsushi
  • Journal Title: Methods Mol Biol Volume: 1904 Pages: 147-162
  • DOI: 10.1007/978-1-4939-8958-4_6
  • ISBN: 9781493989577, 9781493989584
• [Journal Article] A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens (2018)
  • Author(s): Hu Z, Anandappa AJ, Sun J, Kim J, Leet DE, Bozym DJ, Chen C, Williams L, Shukla SA, Zhang W, Tabbaa D, Steelman S, Olive O, Livak KJ, Kishi H, Muraguchi A, Guleria I, Stevens J, Lane WJ, Burkhardt UE, Fritsch EF, Neuberg D, Ott PA, Keskin DB, Hacohen N, Wu CJ
  • Journal Title: Blood Volume: 132 Issue: 18 Pages: 1911-1921
  • DOI: 10.1182/blood-2018-04-843763
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans (2018)
  • Author(s): Tsuda Sayaka、Zhang Xiaoxin、Hamana Hiroshi、Shima Tomoko、Ushijima Akemi、Tsuda Kei、Muraguchi Atsushi、Kishi Hiroyuki、Saito Shigeru
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 1934-1934
  • DOI: 10.3389/fimmu.2018.01934
  • Peer Reviewed / Open Access
• [Journal Article] Introduction of genetically modified CD3ζ improves proliferation and persistence of antigen-specific CTLs. (2018)
  • Author(s): Miyao K, Terakura S, Okuno S, Julamanee J, Watanabe K, Hamana H, Kishi H, Sakemura R, Koyama D, Goto T, Nishida T, Murata M, Kiyoi H.
  • Journal Title: Cancer Immunol Res Volume: 6 Issue: 6 Pages: 733-744
  • DOI: 10.1158/2326-6066.cir-17-0538
  • Peer Reviewed
• [Journal Article] Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis (2018)
  • Author(s): Shitaoka Kiyomi、Hamana Hiroshi、Kishi Hiroyuki、Hayakawa Yoshihiro、Kobayashi Eiji、Sukegawa Kenta、Piao Xiuhong、Lyu Fulian、Nagata Takuya、Sugiyama Daisuke、Nishikawa Hiroyoshi、Tanemura Atsushi、Katayama Ichiro、Murahashi Mutsunori、Takamatsu Yasushi、Tani Kenzaburo、Ozawa Tatsuhiko、Muraguchi Atsushi
  • Journal Title: Cancer Immunology Research Volume: 6 Issue: 4 Pages: 378-388
  • DOI: 10.1158/2326-6066.cir-17-0489
  • Peer Reviewed / Open Access
• [Presentation] The identification of a common loss-function mutation across different HLA class alleles frequently detected in patients with acquired aplastic anemia. (2019)
  • Author(s): Mizumaki H, Hosomichi K, Tanabe M, Yoroidaka T, Imi T, Hosokawa K, Katagiri T, Takamatsu H, Ozawa T, Azuma F, Kishi H, Tajima A, Nakao S.
  • Organizer: 24th Congress of European Hematology Association
  • Int'l Joint Research
• [Presentation] A novel TCR cloning system of peptide-specific T cells using immunospot array assay on a chip(T-ISAAC) technology. (2019)
  • Author(s): Kobayashi E, Ozawa T, Hamana H, Shitaoka K, Muraguchi A, Kishi H.
  • Organizer: International Conference on Lymphocyte Engineering 2019
  • Int'l Joint Research
• [Presentation] TCR repertoire analysis of PD-1- or PD-1+ tumor infiltrating lymphocytes in colorectal cancer and breast cancer: TCR property affects their phenotype. (2019)
  • Author(s): Kishi H.
  • Organizer: 17th International Congress of Immunology
  • Int'l Joint Research
• [Presentation] Identification of T-cell receptors specific to antigens presented by HLA-B4002 and B5401 in acquired aplastic anemia. (2019)
  • Author(s): Hosokawa K, Kobayashi E, Akatsuka Y, Espinoza L, Nakagawa N, Tanabe M, Tsuji N, Yoroidaka T, Mizumaki H, Mai A.T.N., Katagiri T, Shitaoka K, Hamana H, Kishi H, Nakao S.
  • Organizer: 61st Annual Meetings of American Society of Hematology
  • Int'l Joint Research
• [Presentation] 患者HLA遺伝子導入乳がん細胞株を用いた乳がん患者TIL中の腫瘍反応性TCRの探索． (2019)
  • Author(s): 浜名 洋，下岡 清美，祐川 健太，佐伯しおり，長田任一哉，小林 栄治，小澤 龍彦，藤井 努，村口 篤，岸 裕幸．
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] 腫瘍浸潤CD8+ T細胞におけるPD-1の発現はTCRレパトアに規定される． (2019)
  • Author(s): 祐川 健太，佐伯しおり，下岡 清美，浜名 洋，宮原 慶裕，小林 栄治，長田任一哉，小澤 龍彦，藤井 努，珠玖 洋，村口 篤，岸 裕幸．
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Clonally expanded populations of cytotoxic T cell in TILs and peripheral blood in endometrial cancer patients. (2019)
  • Author(s): 津田 桂，浜名 洋，中島 彰俊，森田 恵子，津田さやか，島 友子，下岡 清美，小林 栄治，小澤 龍彦，村口 篤，岸 裕幸．
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] 腫瘍浸潤CD8+ T細胞のTCRとPD-1の発現との関連：大腸癌における考察． (2019)
  • Author(s): 岸 裕幸，祐川 健太，下岡 清美，浜名 洋，小林 栄治，津田 桂，長田任一哉，佐伯しおり，小澤 龍彦，齋藤 滋，藤井 努，村口 篤．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 腫瘍反応性TIL由来TCRおよびその認識抗原を用いた個別化がん免疫療法の展望． (2019)
  • Author(s): 宮原 慶裕，問山 裕二，北嶋 貴仁，浜名 洋，楠 正人，井上 正宏，岸 裕幸，珠玖 洋．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Identification of T cell receptors specific to antigens presented by HLA-B4002 in aplastic anemia. (2019)
  • Author(s): Hosokawa K, Kobayashi E, Akatsuka Y, Espinoza L, Nakagawa N, Tanabe M, Tsuji N, Yoroidaka T, Mizukami H, Mai A. T. N, Katagiri T, Shitaoka K, Hamana H, Kishi H, Nakao S.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] ISAAC法を用いたTCR様抗体の迅速単離法の開発． (2019)
  • Author(s): 小澤 龍彦，呂 福蓮，村口 篤，岸 裕幸．
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Screening of tumor-reactive TCRs from TILs of breast cancer patients using a patients' HLA-transduced breast cancer cell line. (2019)
  • Author(s): Hamana H, Shitaoka K, Sukegawa K, Saeki S, Nagata T, Kobayashi E, Ozawa T, Fujii T, Muraguchi A, Kishi H.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] Common TCR-beta repertoire was found in both decidual and peripheral CD8+ T cells in normal term pregnancy. (2019)
  • Author(s): Morita K, Kobayashi E, Tsuda S, Shitaoka K, Ozawa T, Hamana H, Saito S, Kishi H.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] Cloning of tumor antigen-specific TCRs using immunospot array assay on a chip (T-ISAAC) technology. (2019)
  • Author(s): Kobayashi E, Ozawa T, Hamana H, Shitaoka K, Muraguchi A, Kishi H.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] A new epitope is identified derived from envelope protein of an endogenous murine leukemia virus. (2019)
  • Author(s): Shitaoka K, Hamana H, Muraguchi A, Kishi H.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] TCR repertoire analysis of cytotoxic T cells in tumor-infiltrated lymphocytes and peripheral blood lymphocytes in endometrial cancers. (2019)
  • Author(s): Tsuda K, Hamana H, Nakashima A, Tsuda S, Shima T, Shitaoka K, Kobayashi E, Ozawa T, Kishi H.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] CTL lines specific for a wild type tumor antigen exert tumor regulatory activity in vivo. (2019)
  • Author(s): Kasai M, Komatsu T, Sakaguti N, Kishi H, Udaka K.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] NKG2D as a marker of active tumor-antigen specific CD8+ T cells during antitumor immune response. (2019)
  • Author(s): Ucche S, Mojic M, Shitaoka K, Kishi H, Muraguchi A, Tahara H, Hayakawa Y.
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] Clonally expanded decidual effector Treg cells increase in late gestation of normal pregnancy, but not in preeclampsia in human. (2018)
  • Author(s): Tsuda S, Kishi H, Xiaoxin Z, Shima T, Hamana H, Tsuda K, Ushijima A, Muraguchi A, Saito S.
  • Organizer: The 38th Annual Meeting of the American Society for Reproductive Immunology
  • Int'l Joint Research
• [Presentation] Clonally expanded populations of cytotoxic T cell in tumor infiltrated lymphocyte and peripheral blood in endometrial cancer. (2018)
  • Author(s): Tsuda K, Kishi H, Nakashima A, Hamana H, Ushijima A, Tsuda S, Shima T, Shitaoka K, Kobayashi E, Ozawa T, Yoshino O, Saito S.
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] マウス腫瘍細胞株をモデルとした高免疫原性変異抗原の同定とワクチン治療への応用． (2018)
  • Author(s): 宮原慶裕，藤井啓介，金関貴幸，鳥越俊彦，山口 類，井元清哉，宮野 悟，浜名 洋，岸 裕幸，珠玖 洋．
  • Organizer: 第22回日本がん免疫学会学術総会
• [Presentation] T-ISAAC法を用いたペプチド特異的T細胞のTCRレパトア解析． (2018)
  • Author(s): 小林栄治，村口 篤，岸 裕幸．
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] TILでクローナルなT細胞受容体は，腫瘍に対して細胞障害性を示し，腫瘍関連抗原を認識する． (2018)
  • Author(s): 下岡清美，浜名 洋，小林栄治，早川芳弘，村口 篤，岸 裕幸．
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] ヒト大腸がん組織に浸潤する腫瘍反応性CD8陽性T細胞の表現型および遺伝子解析． (2018)
  • Author(s): 宮原慶裕，藤井啓介，問山裕二，北嶋貴仁，井上靖浩，浜名 洋，遠藤洋子，楠 正人，井上正宏，岸 裕幸，珠玖 洋．
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] CTLとTh細胞を共に活性化できる膀胱癌関連抗原に由来する長鎖ペプチドの同定． (2018)
  • Author(s): 鶴田未季，平山正敏，Poh Yin Yew，吉村祥子，岸 裕幸，浜名 洋，千住 覚，入江 厚，矢津田旬二，神波大己，江藤正俊，中山秀樹，西村泰治．
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 効率的な大腸癌免疫療法の確立に向けた腫瘍浸潤リンパ球レパートリー解析． (2018)
  • Author(s): 祐川健太，浜名 洋，下岡清美，小林栄治，北條荘三，奧村知之，長田拓哉，村口 篤，岸 裕幸，藤井 努．
  • Organizer: 第29回日本消化器癌発生学会総会
• [Presentation] 制御性T細胞のsingle-cell TCRレパートリー解析により示唆された流産と妊娠高血圧腎症の免疫学的病態の相違． (2018)
  • Author(s): 津田さやか，チャン シャオシン，浜名 洋，島 友子，牛島明美，津田 桂，村口 篤，岸 裕幸，齋藤 滋．
  • Organizer: 第33回日本生殖免疫学会総会・学術集会
• [Presentation] 子宮体癌患者における末梢血CD8T細胞のTCRレパートリー解析． (2018)
  • Author(s): 津田 桂，岸 裕幸，中島彰俊，浜名 洋，牛島明美，津田さやか，島 友子，下岡清美，小林栄治，小澤龍彦，吉野 修，齋藤 滋．
  • Organizer: 第33回日本生殖免疫学会総会・学術集会
• [Presentation] 酵母表面ディスプレイ法を用いたTCRの抗原ペプチド/MHCライブラリーの作製とそのスクリーニング． (2018)
  • Author(s): 小澤龍彦，大貫 燿，浜名 洋，小林栄治，呂 福蓮，村口 篤，岸 裕幸．
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] TCR repertoire analysis of peptide-specific T cells using immunospot array assay on a chip (T-ISAAC) technology. (2018)
  • Author(s): Kobayashi E, Ozawa T, Hamana H, Shitaoka K, Muraguchi A, Kishi H.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] A rapid and simple protocol for cDNA cloning of tumor antigen-specific TCR. (2018)
  • Author(s): Hamana H, Ozawa T, Kobayashi E, Shitaoka K, Muraguchi A, Kishi H.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] The development of antigen detection system using yeast surface display library. (2018)
  • Author(s): Ohnuki Y, Ozawa T, Hamana H, Kobayashi E, Lyu F, Muraguchi A, Kishi H.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Tumor infiltrating lymphocyte repertoire analysis of colon cancer. (2018)
  • Author(s): Sukegawa K, Hamana H, Shitaoka K, Kobayashi E, Saeki S, Nagata T, Fujii T, Muraguchi A, Kishi H.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Clonally expanded populations of cytotoxic T cell in tumor infiltrated lymphocyte and peripheral blood in uterine endometrial cancer. (2018)
  • Author(s): Tsuda K, Kishi H, Nakashima A, Hamana H, Tsuda S, Shima T, Shitaoka K, Kobayashi E, Ozawa T, Muraguchi A, Saito S.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Development of TCR-antigen identification system using “cis-interaction” of TCR and peptide/MHC complex on a T cell. (2018)
  • Author(s): Yamaguchi S, Kishi H, Shitaoka K, Hamana H, Kobayashi E, Ozawa T, Muraguchi A.
  • Organizer: 第47回日本免疫学会学術集会