The mechanism of strong PD-1 expression leading to immuno-suppression.

• Project/Area Number: 25460363
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Keio University (2015); Kyoto University (2013-2014)
• Principal Investigator: CHIKUMA SHUNSUKE 慶應義塾大学, 医学部, 講師 (50437208)
• Co-Investigator(Renkei-kenkyūsha): MIYACHI Hitoshi 京都大学, ウイルス研究所, 技術専門職員 (90599200)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫寛容 / 自己免疫 / がん免疫 / 抑制レセプター / Ｔ細胞 / 抑制受容体 / PD-1 / T細胞 / 遺伝子改変マウス / 免疫疲弊 / 新規マウスモデル

Outline of Final Research Achievements

PD-1 is induced on activated lymphocytes, inhibits their excessive activation, and thereby prevents damage on self-tissues. In durable immune reaction, for example, chronic infection and cancer, PD-1 is super-strongly expressed, which prevents useful immune reaction. The mechanism of the strong PD-1 expression was unclear. In this study, I aimed to determine what causes strong PD-1 expression in vivo. (1) I utilized molecular genetic tools to create a reporter mice that allows faithful detection of PD-1 expression in mice. (2) I found that IL-7, a homeostatic cytokine for lymphocytes negatively regulates PD-1 expression. In a separate line of experiment, I showed PD-1 controls innate immune reaction by inhibiting macrophage activation. The current study will bring a useful information to understand the biology of PD-1.

Research Products

• [Journal Article] Basics of PD-1 in self-tolerance, infection, and cancer immunity. (2016)
  • Author(s): Shunsuke Chikuma
  • Journal Title: Int J Clin Oncol. Volume: Feb 10
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22. (2015)
  • Author(s): Sakaguchi R, Chikuma S, Shichita T, Morita R, Sekiya T, Ouyang W, Ueda T, Seki H, Morisaki H, Yoshimura A
  • Journal Title: Int Immunol. Volume: Dec 8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Safety and Anti-tumor Activity of Anti–PD-1 Antibody (Nivolumab: ONO-4538/BMS-936558) in Patients with Platinum-resistant Ovarian Cancer. (2015)
  • Author(s): Hamanishi, J., M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, T. Murayama, M. Kanai, Y. Mori, S. Matsumoto, S. Chikuma, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, Y. Hosoe, S. Morita, M. Yokode, A. Shimizu, T. Honjo, I. Konishi.
  • Journal Title: J Clin Oncol Volume: 33 Issue: 34 Pages: 4015-22
  • DOI: 10.1200/jco.2015.62.3397
  • Peer Reviewed / Open Access
• [Journal Article] Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function (2014)
  • Author(s): Stumpf M, Zhou X, Chikuma S, Bluestone JA
  • Journal Title: Eur. J. Immunol. Volume: 44 Issue: 6 Pages: 1737-1746
  • DOI: 10.1002/eji.201343891
  • Peer Reviewed
• [Journal Article] Activation-induced cytidine deaminase is dispensable for virus-mediated liver and skin tumor development in mouse models. (2014)
  • Author(s): Nguyen T, Xu J, Chikuma S, Hiai H, Kinoshita K, Moriya K, Koike K, Marcuzzi GP, Pfister H, Honjo T, Kobayashi M.
  • Journal Title: Int Immunol Volume: 26 Issue: 7 Pages: 397-406
  • DOI: 10.1093/intimm/dxu040
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. (2013)
  • Author(s): Rui Y, Honjo T, Chikuma S
  • Journal Title: PNAS Volume: 110 Issue: 40 Pages: 16073-8
  • DOI: 10.1073/pnas.1315828110
  • NAID: 120005324915
  • Peer Reviewed
• [Journal Article] A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. (2013)
  • Author(s): Taku Okazaki, Shunsuke Chikuma, Yoshiko Iwai, Sidonia Fagarasan, Tasuku Honjo.
  • Journal Title: Nat. Immunol. Volume: 14 Issue: 12 Pages: 1212-1218
  • DOI: 10.1038/ni.2762
  • NAID: 120005527992
  • Peer Reviewed
• [Presentation] Analysis of PD-1 expression and function on innate immune cells (2014)
  • Author(s): Chikuma S, Honjo T
  • Organizer: 日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] PD-1 inhibits inflammatory helper T-cell development through controlling the innate immune response (2013)
  • Author(s): Rui Y, Honjo T, Chikuma S
  • Organizer: 日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Remarks] 免疫のブレーキPD-1が、自然免疫反応の調節によって免疫難病の発症を抑制することを解明
  • URL: http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2013/130917_2.htm