Identification of the bone microenvironment that constructs the innate immune system

• Project/Area Number: 19K07604
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kyoto University
• Principal Investigator: Hara Takahiro 京都大学, ウイルス・再生医科学研究所, 助教 (90512301)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄 / ストローマ細胞 / 微小環境

Outline of Research at the Start

自然免疫を担当する免疫細胞には様々な種類があるが、これらの分化を支持する骨微小環境（ニッチ）の性状は明らかになっていない。
本研究では、自然免疫細胞の分化に必須なニッチ構成ストローマ細胞を同定し、分化を支持するサイトカイン（生理活性タンパク質）、ケモカイン（免疫細胞の遊走活性を制御する因子）を明らかにすることを目的とする。

Outline of Final Research Achievements

There are various types of immune cells responsible for innate immunity, and they play an important role in pathological conditions such as infectious immune response, antitumor immunity, and inflammatory diseases. However, it is not clear whether there is diversity in the bone marrow microenvironment that supports the differentiation, maintenance, and response of various innate immune cells. In this study, we found that multiple innate immune cells form a unique positioning within the bone marrow, and that the bone marrow has a "functionally compartmentalized microenvironment" that supports the innate immune cells.

Academic Significance and Societal Importance of the Research Achievements

定常状態においては、骨髄ストローマ細胞がその種類によって異なる自然免疫細胞を支持していることが示唆された。また、慢性炎症疾患などの病態モデルにおいては、自然免疫細胞の誘引・繋留に関与する分子の機能が阻害され、自然免疫細胞の骨髄内での挙動や末梢への動員に変化が起きた。病態時において、骨髄ストローマ細胞の性質が変容する結果が得られたことから、骨髄ストローマ細胞は慢性炎症疾患の治療標的となり得る。

Research Products

• [Journal Article] The roles of IL-7 and IL-15 in niches for lymphocyte progenitors and immune cells in lymphoid organs (2021)
  • Author(s): Ikuta K, Hara T, Abe S, Asahi T, Takami D, Cui G
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 434 Pages: 83-101
  • DOI: 10.1007/978-3-030-86016-5_4
  • ISBN: 9783030860158, 9783030860165
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Innate-like CD27+CD45RBhigh γδ T Cells Require TCR Signaling for Homeostasis in Peripheral Lymphoid Organs. (2020)
  • Author(s): Tani-Ichi S, Wagatsuma K, Hara T, Cui G, Abe S, Miyachi H, Kitano S, Ikuta K.
  • Journal Title: The Journal of Immunology Volume: 204(10) Issue: 10 Pages: 2671-2684
  • DOI: 10.4049/jimmunol.1801243
  • Peer Reviewed
• [Journal Article] IL-7R-Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis. (2020)
  • Author(s): Cui G, Shimba A, Ma G, Takahara K, Tani-Ichi S, Zhu Y, Asahi T, Abe A, Miyachi H, Kitano S, Hara T, Yasunaga JI, Suwanai H, Yamada H, Matsuoka M, Ueki K, Yoshikai Y, Ikuta K.
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 4 Pages: 844-857
  • DOI: 10.4049/jimmunol.1900456
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mesenchymal stromal cells in bone marrow express adiponectin and are efficiently targeted by an adiponectin promoter-driven Cre transgene. (2019)
  • Author(s): Mukohira H, Hara T, Abe S, Tani-Ichi S, Sehara-Fujisawa A, Nagasawa T, Tobe K, Ikuta K.
  • Journal Title: International Immunology Volume: 31 Issue: 11 Pages: 729-742
  • DOI: 10.1093/intimm/dxz042
  • NAID: 120006872738
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine (2019)
  • Author(s): Zhu Yuanbo、Cui Guangwei、Miyauchi Eiji、Nakanishi Yuki、Mukohira Hisa、Shimba Akihiro、Abe Shinya、Tani-ichi Shizue、Hara Takahiro、Nakase Hiroshi、Chiba Tsutomu、Sehara-Fujisawa Atsuko、Seno Hiroshi、Ohno Hiroshi、Ikuta Koichi
  • Journal Title: International Immunology Volume: 32 Issue: 5 Pages: 307-319
  • DOI: 10.1093/intimm/dxz082
  • NAID: 120006846480
  • Peer Reviewed
• [Presentation] Identification of the gut microenvironment by the cytokine reporter mice (2021)
  • Author(s): Hara T
  • Organizer: 第94回 日本生化学会大会
• [Presentation] The cytokine-producing immune microenvironment for innate lymphocytes (2019)
  • Author(s): Koichi Ikuta, Guangwei Cui, Shinya Abe, Takuma Asahi, Takahiro Hara
  • Organizer: 第48回 日本免疫学会学術集会（アクトシティ浜松）
• [Presentation] Function of IL-7Rα in regulatory T cells (2019)
  • Author(s): Shizue Tani-ichi, Hisa Mukohira, Takahiro Hara, Koichi Ikuta
  • Organizer: 第48回 日本免疫学会学術集会（アクトシティ浜松）
• [Presentation] Estrogens suppress T cell production by a TEC-dependent mechanism (2019)
  • Author(s): Shinya Abe, Aki Ejima, Akihiro Shimba, Mizuki Mori, Guangwei Cui, Takuma Asahi, Daichi Takami, Takahiro Hara, Shizue Tani-ichi, Koichi Ikuta
  • Organizer: 第48回 日本免疫学会学術集会（アクトシティ浜松）
• [Presentation] Role of local IL-7 in maintenance of lung ILC2s (2019)
  • Author(s): Daichi Takami, Shinya Abe, Akihiro Shimba, Takuma Asahi, Yuanbo Zhu, Aki Ejima, Shizue Tani-ichi, Takahiro Hara, Guangwei Cui, Koichi Ikuta
  • Organizer: 第48回 日本免疫学会学術集会（アクトシティ浜松）
• [Presentation] NK細胞の分化を支持するIL-15産生性骨髄微小環境の解明 (2019)
  • Author(s): 阿部真也、原崇裕、崔広為、生田宏一
  • Organizer: 第29回 Kyoto T Cell Conference（芝蘭会館）
• [Remarks] 京都大学 医生物学研究所
  • URL: https://www.infront.kyoto-u.ac.jp/
• [Remarks] ウイルス感染研究部門 免疫制御分野
  • URL: https://www.infront.kyoto-u.ac.jp/laboratory/lab07/
• [Remarks] 京都大学ウイルス・再生医科学研究所
  • URL: https://www.infront.kyoto-u.ac.jp/
• [Remarks] ウイルス感染研究部門免疫制御分野
  • URL: https://www.infront.kyoto-u.ac.jp/research/lab07/
• [Remarks] 京都大学 ウイルス・再生医科学研究所
  • URL: https://www.infront.kyoto-u.ac.jp/
• [Remarks] ウイルス感染研究部門 免疫制御分野
  • URL: https://www.infront.kyoto-u.ac.jp/research/lab07/