Investigation of molecular mechanism for serial transmission of tolerant status of T cells -Role of CD155 transducing signaling mediated by TIGIT-

• Project/Area Number: 19K18041
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Juntendo University
• Principal Investigator: NEGISHI Naoko 順天堂大学, 大学院医学研究科, 特任助教 (40784294)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: TIGIT / トレランスの伝承 / 抗原特異的免疫寛容 / IL-2/IL-2レセプター / CD155 / Treg細胞 / 免疫チェックポイント / IL-2/IL-2R / STAT5 / 免疫寛容 / Treg / 制御性T細胞 / IL-2 / T細胞 / 免疫チェックポイント分子 / 移植

Outline of Research at the Start

移植した細胞や組織を生着・機能させるためには、レシピエントにおける免疫寛容が移植片に特異的且つ寛容状態が長期にわたって維持される抗原特異的免疫寛容の誘導が重要であるがそれらの分子機構は未だ不明である。
申請者らは抗原特異的T細胞の抑制機能が連続的に伝達するためにはTIGIT (T cell Ig like receptor and ITIM domain) が重要な役割を果たす事を見いだした。
本研究では、抗原特異的抑制性T細胞の生存・維持及び伝達機構におけるTIGITの役割と機序解明を目指す。それら知見に基づいて、新たな移植治療法や自己免疫疾患治療法開発を目指す。

Outline of Final Research Achievements

In this study, we investigated how CD155-mediated signaling induce TIGIT expression in stimulated naive T cells, leading to suppressive function、based on the expression status of TIGIT, key molecules of “infectious tolerance”. we showed, CD3/CD155 double ligated T cells through IL-2/IL-2R - STAT5 axis by rapid expression of IL-2 which leads to the induction of downstream IL-2 expression inhibitory genes , resulting in IL-2 down reguration.　Additionally, we found that the upregulation of TIGIT expression in CD3/CD155 double ligated T cells occurs through rapid expression of IL-2.
We transfered TIGIT highly expressed on the tolerant T cells into recipent mouse, result in T cells from recipient mice were suppressed IL-2 expression.
Currently, We are going to confirm that the newly enhanced TIGIT is substantially from the past TIGIT expressing cells or newly stimulated and proliferated cells by using a reporter mouse strain taking advantage of TIGIT promoter-driven Cre recombinase.

Academic Significance and Societal Importance of the Research Achievements

本研究により、抑制性T細胞のTIGITの発現維持の証明が今まで困難であったin vitro及びin vivo系の両方を使った検証が可能となった。さらに、本研究成果は今まで不明であった免疫記憶の成立と維持機構の解明といった免疫発生学分野に重要な知見をもたらす。
本研究により、TIGITーCD155シグナルが免疫抑制機能を伝達に重要であることが明らかになったことで、TIGITーCD155をターゲットとした移植片に対する寛容誘導に関する細胞治療や診断法の開発、アレルギーや自己免疫疾患の治療開発にも重要な知見と情報をもたらす。

Research Products

• [Journal Article] Anti-CD80/86 antibodies inhibit inflammatory reaction and improve graft survival in a high-risk murine corneal transplantation rejection model (2022)
  • Author(s): Zhu J, Inomata T, Nakamura M, Fujimoto K, Akasaki Y, Fujio K, Yanagawa A, Uchida K, Sung J, Negishi N, Nagino K, Okumura Y, Miura M, Shokirova H, Kuwahara M, Hirosawa K, Midorikawa-Inomata A, Eguchi A, Huang T, Yagita H, Habu S, Okumura K, Murakami A.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 4853-4853
  • DOI: 10.1038/s41598-022-08949-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ex Vivo?Induced Bone Marrow-Derived Myeloid Suppressor Cells Prevent Corneal Allograft Rejection in Mice (2021)
  • Author(s): Zhu Jun、Inomata Takenori、Fujimoto Keiichi、Uchida Koichiro、Fujio Kenta、Nagino Ken、Miura Maria、Negishi Naoko、Okumura Yuichi、Akasaki Yasutsugu、Hirosawa Kunihiko、Kuwahara Mizu、Eguchi Atsuko、Shokirova Hurramhon、Yanagawa Ai、Midorikawa-Inomata Akie、Murakami Akira
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 62 Issue: 7 Pages: 3-3
  • DOI: 10.1167/iovs.62.7.3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel immunotherapeutic effects of topically administered ripasudil (K-115) on corneal allograft survival (2020)
  • Author(s): Inomata Takenori、Fujimoto Keiichi、Okumura Yuichi、Zhu Jun、Fujio Kenta、Shokirova Hurramhon、Miura Maria、Okano Mikiko、Funaki Toshinari、Sung Jaemyoung、Negishi Naoko、Murakami Akira
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 19817-19817
  • DOI: 10.1038/s41598-020-76882-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD300f is a potential therapeutic target for the treatment of food allergy (2019)
  • Author(s): Uchida Shino、Izawa Kumi、Ando Tomoaki、Yamada Hiromichi、Uchida Koichiro、Negishi Naoko、Kaitani Ayako、Maehara Akie、Nagamine Masakazu、Kamei Anna、Takamori Ayako、Maeda Keiko、Nakano Nobuhiro、Shimizu Toshiaki、Ogawa Hideoki、Okumura Ko、Nagahara Akihito、Watanabe Sumio、Kitaura Jiro
  • Journal Title: Allergy Volume: 75 Issue: 2 Pages: 471-474
  • DOI: 10.1111/all.14034
  • NAID: 40022209298
  • Peer Reviewed / Open Access
• [Presentation] Suppressive function in TIGIT+ iTreg cells is serially transmitted into newstimulated T cells via CD 155 signaling with recall of TIGIT expression. (2022)
  • Author(s): 根岸尚子, 内田浩一郎, 渋谷和子, 北浦次郎, 奥村康 、垣生園子
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] TIGIT plays a critical role as a ligand for inducing CD155 mediated suppressor potential to be tolerance (2021)
  • Author(s): 根岸尚子、佐藤健人、渋谷和子、内田浩一郎、亀谷美恵、北浦次郎、奥村康、垣生園子
  • Organizer: 第 50 回日本免疫学会学術集会
• [Presentation] Tolerant status of T cells via TIGIT-CD155 axis is transferable in vivo (2019)
  • Author(s): 根岸尚子、佐藤健人、金丸由美、渋谷和子、内田浩一郎、亀谷美恵、奥村康、垣生園子
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] 免疫寛容を伝達する分子機構 ー CD4+ T 細胞の抑制機能の伝承はTIGIT→CD155経路を介するー (2019)
  • Author(s): 根岸尚子, 垣生園子
  • Organizer: 第29回 Kyoto T Cell Conference
• [Presentation] “Infectious suppression”の機序ーTIGIT->CD155シグナルを介して伝承されるT細胞の抑制機能は生体内でも誘導されるー (2019)
  • Author(s): 根岸尚子
  • Organizer: 第34回 自己免疫研究会