IL-15-producing microenvironment supporting innate lymphoid cells and its role in diseases

• Project/Area Number: 20H03501
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kyoto University
• Principal Investigator: Ikuta Koichi 京都大学, 医生物学研究所, 教授 (90193177)
• Co-Investigator(Kenkyū-buntansha): 榛葉 旭恒 京都大学, 医学研究科, 助教 (30812242) ; 谷一 靖江 京都大学, 医学研究科, 特定講師 (50432331) ; 崔 广為 京都大学, 医生物学研究所, 助教 (70791276)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 自然免疫 / サイトカイン / 微小環境 / IL-15 / 腫瘍免疫

Outline of Research at the Start

自然リンパ球、NK細胞、NKT細胞などの自然免疫系リンパ球は感染免疫応答、抗腫瘍免疫、炎症免疫疾患などにおいて重要である。これらを制御するためには、自然免疫系リンパ球の生成と機能の調節機構を解明することが必要である。自然免疫系リンパ球の分化・維持・機能にはサイトカインIL-15が必須である。しかし、自然免疫系リンパ球がどのような細胞に依存するのかという問題は未解決である。本研究は、独自に作製した細胞特異的IL-15欠損マウスを用いて、NK細胞とNKT細胞の分化・維持・機能を支える骨髄と胸腺のIL-15産生性免疫微小環境を同定し、その感染防御・抗腫瘍免疫・慢性炎症における機能を明らかにする。

Outline of Final Research Achievements

Innate-like lymphocytes such as NK and NKT cells play pivotal roles in infectious immune responses, antitumor immunity, and inflammatory immune diseases. In this study, we identified IL-15-producing cells that support the differentiation, maintenance, and function of NK and NKT cells and clarified their functions. First, we demonstrated the reliance of NK cells on IL-15 derived from hematopoietic cells within the bone marrow for their differentiation. Furthermore, we have discerned two distinct subsets of bone marrow NK cells: scattered and clustered, with CXCL12 emerging as a critical factor in the distribution of the scattered population. Additionally, we have established the dependence of CD244+ iNKT cells on IL-15 produced by thymic epithelial cells for their differentiation. Notably, this subset exhibits elevated levels of IFN-g, akin to NK cells, and plays an important role in tumor cell elimination.

Academic Significance and Societal Importance of the Research Achievements

自然免疫系リンパ球は、感染免疫応答、抗腫瘍免疫、炎症免疫疾患において重要な働きをしているが、その分化や機能を支える微小環境については不明であった。本研究では、NK細胞が骨髄造血細胞のIL-15に依存して分化する発見から、造血細胞の分化を他の造血細胞が支持するという新規概念の提唱に発展した。また、散在型とクラスター型の２種類のNK細胞の発見から、NK細胞が機能の異なるサブセットに分かれている可能性が想起された。さらに、CD244陽性iNKT細胞は通常型iNKT細胞とは異なり全身循環性であることから、iNKT細胞も機能的に異なるサブセットに分かれている可能性が示された。

Research Products

• [Journal Article] Retinoic acid receptor activity is required for the maintenance of type 1 innate lymphoid cells (2023)
  • Author(s): Asahi, T., Abe, S., Tajika, Y., Rodewald, H. R., Sexl, V., Takeshima, H., and Ikuta, K.
  • Journal Title: Int. Immunol. Volume: 35 Issue: 3 Pages: 147-155
  • DOI: 10.1093/intimm/dxac057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-throughput identification and quantification of single bacterial cells in the microbiota (2022)
  • Author(s): Jin, J., Yamamoto, R., Takeuchi, T., Cui, G., Miyauchi, E., Hojo, N., Ikuta, K., Ohno, H., and Shiroguchi, K.
  • Journal Title: Nat. Commun. Volume: 13 Issue: 1 Pages: 863-863
  • DOI: 10.1038/s41467-022-28426-1
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies (2022)
  • Author(s): Kansler, E. R., Dadi,S., Krishna, C., Nixon, B. G., Stamatiades E. G., Liu, M., Kuo, F., Zhang, J., Zhang, X., Capistrano, K., Blum, K. A., Weiss, K., Kedl, R. M., Cui, G., Ikuta, K., Chan, T. A., Leslie, C. S., Hakimi, A. A. and Li, M. O.
  • Journal Title: Nat. Immunol. Volume: 23 Issue: 6 Pages: 904-915
  • DOI: 10.1038/s41590-022-01213-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Estradiol suppresses psoriatic inflammation in mice by regulating neutrophil and macrophage functions (2022)
  • Author(s): Adachi Akimasa、Honda Tetsuya、Egawa Gyohei、Kanameishi Shuto、Takimoto Riko、Miyake Toshiya、Hossain Md Razib、Komine Mayumi、Ohtsuki Mamitaro、Gunzer Matthias、Ikuta Koichi、Kabashima Kenji
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 150 Issue: 4 Pages: 909-919.e8
  • DOI: 10.1016/j.jaci.2022.03.028
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity (2022)
  • Author(s): Das Gupta, D., Paul, C., Samel, N., Bieringer, M., Staudenraus, D., Marini, F., Raifer, H., Menke, L., （８人） Helmprobst, F., Buchholz, M., Roth, K., Bastian, L., Hartmann, A. M., Baldus, C., Ikuta, K., Neubauer, A., Burchert, A., Jack, H-M., Klein, M., Bopp, T., Stiewe, T., Pagenstecher, A., and Lohoff, M.
  • Journal Title: Cell Death Differ. Volume: 29 Issue: 11 Pages: 2163-2176
  • DOI: 10.1038/s41418-022-01005-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production in Th2 Cells (2022)
  • Author(s): Ejima Aki、Abe Shinya、Shimba Akihiro、Sato Susumu、Uehata Takuya、Tani-ichi Shizue、Munakata Satoru、Cui Guangwei、Takeuchi Osamu、Hirai Toyohiro、Kato Shigeaki、Ikuta Koichi
  • Journal Title: The Journal of Immunology Volume: 209 Issue: 6 Pages: 1083-1094
  • DOI: 10.4049/jimmunol.2200294
  • Peer Reviewed
• [Journal Article] Interleukin-7 receptor signaling is crucial for enhancer-dependent TCRd germline transcription mediated through STAT5 recruitment (2022)
  • Author(s): Rodriguez-Caparros, A., Tani-ichi, S., Casal, A., Lopez-Ros, J., Sune, C., Ikuta, K., and Hernandez-Munain, C.
  • Journal Title: Front. Immunol. Volume: 13 Pages: 943510-943510
  • DOI: 10.3389/fimmu.2022.943510
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A circulating subset of iNKT cells mediates antitumor and antiviral immunity (2022)
  • Author(s): Cui G, Shimba A, et.al
  • Journal Title: Science Immunology Volume: 7 Issue: 76 Pages: 8760-8760
  • DOI: 10.1126/sciimmunol.abj8760
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks (2022)
  • Author(s): Akter Salma、Shimba Akihiro、Ikuta Koichi、Mahmud Md. Rasel Al、Yamada Shintaro、Sasanuma Hiroyuki、Tsuda Masataka、Sone Masakatsu、Ago Yukio、Murai Kenichi、Tanaka Hisashi、Takeda Shunichi
  • Journal Title: Genes to Cells Volume: 28 Issue: 1 Pages: 53-67
  • DOI: 10.1111/gtc.12993
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids (2021)
  • Author(s): Adachi, A., Honda, T., Dainichi, T., Egawa, G., Yamamoto, Y., Nomura, T., Nakajima, S., Otsuka, A., Maekawa, M., Mano, N., Koyanagi, N., Kawaguchi, Y., Ohteki, T., Nagasawa, T., Ikuta, K., Kitoh, A., and Kabashima, K.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 148 Issue: 6 Pages: 1575-1588.e7
  • DOI: 10.1016/j.jaci.2021.04.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fate of adipocyte progenitors during adipogenesis in mice fed a high-fat diet (2021)
  • Author(s): Bilal M, Nawaz A, Kado T, Rahil Aslam M, Igarashi Y, Nishimura A, Watanabe A, Kuwano T, Liu J, Miwa H, Era T, Ikuta K, Imura J, Yagi K, Nakagawa T, Fujisaka S, Tobe K.
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101328-101328
  • DOI: 10.1016/j.molmet.2021.101328
  • Peer Reviewed / Open Access
• [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] Lymph node stromal cells: diverse meshwork structures weave functionally subdivided niches (2021)
  • Author(s): Takeuchi, A., Ozawa, M., Cui, G., Ikuta, K., and Katakai, T.
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 434 Pages: 103-121
  • DOI: 10.1007/978-3-030-86016-5_5
  • ISBN: 9783030860158, 9783030860165
  • Peer Reviewed
• [Journal Article] IL-4 producing Vg1+/Vd6+ gd T cells sustain germinal center reactions in Peyer's patches of mice (2021)
  • Author(s): Ullrich, L., Lueder, Y., Juergens, A.-L., Wilharm, A., Barros-Martins, J., Bubke, A., Demera, A., Ikuta, K., Patzer, G. E., Janssen, A., Sandrock, I., Prinz, I., and Rampoldi, F.
  • Journal Title: Front. Immunol. Volume: 12 Pages: 729607-729607
  • DOI: 10.3389/fimmu.2021.729607
  • 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] 新規末梢循環型iNKT細胞の同定と機能解析 (2022)
  • Author(s): 崔広為、生田宏一
  • Organizer: Kyoto T Cell Conference 第31回学術集会
• [Presentation] Lung local IL-7 affect the maintenance, distribution, and activation of ILC2 in allergic airway inflammations (2022)
  • Author(s): Daichi Takami, Shinya Abe, Akihiro Shimba, Takuma Asahi, Guangwei Cui, Shizue Tani-ichi, Takahiro Hara, and Koichi Ikuta
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Hepatic ILC1s lacking IL-7 receptor arise independently of conventional group 1 ILCs through parenchymal niches (2022)
  • Author(s): Takuma Asahi, and Koichi Ikuta
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] 胎児肝臓に由来する1型自然リンパ球の同定 (2021)
  • Author(s): 旭拓真、阿部真也、崔広為、榛葉旭恒、生田宏一
  • Organizer: Kyoto T Cell Conference 第30回学術集会
• [Presentation] ストレスはグルココルチコイドを介してTh17細胞の分化を促進し腸炎を増悪させる (2021)
  • Author(s): 榛葉旭恒、生田宏一
  • Organizer: Kyoto T Cell Conference 第30回学術集会
• [Presentation] ステロイドホルモンによる免疫機能とアレルギーの制御 (2021)
  • Author(s): 生田宏一、榛葉旭恒、江島亜希
  • Organizer: 日本アレルギー学会学術集会
  • Invited
• [Remarks] 新規の循環型iNKT細胞を発見―抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待―
  • URL: https://www.kyoto-u.ac.jp/ja/research-news/2022-10-24
• [Remarks] 新規の循環型iNKT細胞を発見―抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待―
  • URL: https://www.infront.kyoto-u.ac.jp/post-3174/