Elucidation of the mechanisms in the strain specific Th2 response in BALB/c mice

• Project/Area Number: 20K21522
• 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: Kanazawa University
• Principal Investigator: Watarai Hiroshi 金沢大学, 医学系, 教授 (70415339)
• Project Period (FY): 2020-07-30 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: iNKT細胞 / Th2 / アレルギー / Th1/Th2 / CD1d / 自然Tリンパ球 / 免疫バランス / 免疫応答 / 疾患モデル

Outline of Research at the Start

これまでTh1/Th2バランスなどの免疫反応の調節は、シグナル伝達や転写因子、サイトカイ
ン応答を伴う細胞間コミュニケーションや相互作用を中心に明らかにされ議論されてきた。
本研究課題はBALB/cマウスがTh2免疫応答を起こしやすい理由がB6には存在しない免疫細胞
による制御機構であることを示そうとするものであり、これまでの免疫学研究とは一線を画し挑戦的である。BALB/cマウスで新しく見つかったIL-17RB依存的iNKT2細胞の存在意義や病態との関連性を明らかにしていく。

Outline of Final Research Achievements

It is well known that BALB/c mice have a dominant Th2 response compared to C57BL/6 mice, but the details of this phenomenon are largely unknown. Since iNKT2 subsets are significantly abundant in iNKT cells in BALB/c mice, we established IL-17RB-deficient mice from both backgrounds and analyzed the differences in their developmental pathways. IL-17RB-deficient mice with a B6 background showed a marked decrease in iNKT2 cells in both periphery and thymus, suggesting that IL-25/IL-17RB axis is essential for development and maintenance. Interestingly however there was no significant difference in the number of iNKT2 cells in the periphery of BALB/c background. In the thymus of BALB/c background, a significant increase of iNKT cells was observed in IL-17RB-deficient mice. The increased population was distinct from iNKT1/2/17 subsets and phenotypically RORγt+ PLZFint T-bet- CD24+ CD44int CD69-, a precursor iNKT2-like cells are appeared.

Academic Significance and Societal Importance of the Research Achievements

BALB/cマウスにはB6マウスに存在しないiNKT2サブセットが存在し、iNKT2サブセットはIL-17RB非依存的に分化発生し得ることを明らかとした。iNKT2細胞は（特に小児期に）様々なアレルギー炎症に関与していることが知られるため、その機能や分化発生経路の一端を明らかにできたことは学術的に意義深い。また遺伝的背景の相違によって異なるiNKT2細胞が分化発生するという結果は、標的となる細胞に個人差があるという裏付けとなるため、様々なアレルギー治療やその制御戦略上重要であり、その社会的要請や意義も高いと考えられる。

Research Products

• [Journal Article] Photoswitching CD1d-restriction of TCR by α-GalCer analogs with azobenzene in the middle of acyl chain (2024)
  • Author(s): Kanamori Takashi、Nakabun Daisuke、Kojo Satoshi、Watarai Hiroshi、Yuasa Hideya
  • Journal Title: Journal of Photochemistry and Photobiology A: Chemistry Volume: 451 Pages: 115501-115501
  • DOI: 10.1016/j.jphotochem.2024.115501
  • Peer Reviewed
• [Journal Article] Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer (2023)
  • Author(s): Nishio Kumiko、Pasquet Lise、Camara Kaddy、DiSapio Julia、Hsu Kevin S.、Kato Shingo、Bloom Anja、Richardson Stewart K.、Welsh Joshua A.、Jiang Tianbo、Jones Jennifer C.、Cardell Susanna、Watarai Hiroshi、Terabe Masaki、Olkhanud Purevdorj B.、Howell Amy R.、Berzofsky Jay A.
  • Journal Title: Journal of Clinical Investigation Volume: 134 Issue: 4
  • DOI: 10.1172/jci165281
  • 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] Early Activation of iNKT Cells Increased Survival Time of BALB/c Mice in a Murine Model of Melioidosis (2022)
  • Author(s): Kasetthat Thitinan、Kamuthachad Ludthawun、Sermswan Rasana W.、Watarai Hiroshi、Matangkasombut Ponpan、Wongratanacheewin Surasakdi
  • Journal Title: Infection and Immunity Volume: 90 Issue: 12
  • DOI: 10.1128/iai.00268-22
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Invariant Natural Killer T (iNKT) cells response in human melioidosis (2022)
  • Author(s): Kamuthachad L, Pisuttimarn P, Kasetthat T, Chetchotisakd P, Anunnatsiri S, Sermswan RW, Watarai H, Matangkasombut P, Wongratanacheewin S.
  • Journal Title: Asian Pacific Journal of Allergy and Immunology Volume: 16 Pages: 166-166
  • DOI: 10.12932/ap-290821-1217
  • Peer Reviewed
• [Journal Article] Correction: Expression of signal-transducing adaptor protein-1 attenuates experimental autoimmune hepatitis via down-regulating activation and homeostasis of invariant natural killer T cells (2021)
  • Author(s): Kashiwakura Jun-ichi、Saitoh Kodai、Ihara Takeru、Sasaki Yuto、Kagohashi Kota、Enohara Shiyo、Morioka Yuka、Watarai Hiroshi、Muromoto Ryuta、Kitai Yuichi、Iwabuchi Kazuya、Oritani Kenji、Matsuda Tadashi
  • Journal Title: PLOS ONE Volume: 16 Issue: 4 Pages: e0250536-e0250536
  • DOI: 10.1371/journal.pone.0250536
  • Peer Reviewed
• [Journal Article] Structure Elucidation of Calyxoside B, a Bipolar Sphingolipid from a Marine Sponge Cladocroce sp. through the Use of Beckmann Rearrangement (2021)
  • Author(s): Sugawara Kenji、Watarai Hiroshi、Ise Yuji、Yokose Hisayoshi、Morii Yasuhiro、Yamawaki Nobuhiro、Okada Shigeru、Matsunaga Shigeki
  • Journal Title: Marine Drugs Volume: 19 Issue: 6 Pages: 287-287
  • DOI: 10.3390/md19060287
  • Peer Reviewed
• [Journal Article] An accumulation of two populations of dendritic cells in skin-draining lymph nodes in response to the expression of thymic stromal lymphopoietin in the skin (2020)
  • Author(s): Omori-Miyake Miyuki、Watarai Hiroshi、Sato Kayoko、Ziegler Steven F.、Yagi Junji
  • Journal Title: Cellular Immunology Volume: 353 Pages: 104116-104116
  • DOI: 10.1016/j.cellimm.2020.104116
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sequentially addressable dielectrophoretic array for high-throughput sorting of large-volume biological compartments (2020)
  • Author(s): A Isozaki, Y Nakagawa, M H Loo, Y Shibata, N Tanaka, D L Setyaningrum, J-W Park, Y Shirasaki, H Mikami, D Huang, H Tsoi, C T Riche, T Ota, H Miwa, Y Kanda, T Ito, K Yamada, O Iwata, K Suzuki, S Ohnuki, Y Ohya, Y Kato, T Hasunuma, S Matsusaka, M Yamagishi, M Yazawa, S Uemura, K Nagasawa, H Watarai, D Di Carlo, K Goda
  • Journal Title: Science Advances Volume: 29 Issue: 22 Pages: 1-11
  • DOI: 10.1126/sciadv.aba6712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Raman image-activated cell sorting. (2020)
  • Author(s): Nitta et al.
  • Journal Title: Nature communications Volume: 11 Issue: 1 Pages: 3452-3452
  • DOI: 10.1038/s41467-020-17285-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of signal-transducing adaptor protein-1 attenuates experimental autoimmune hepatitis via down-regulating activation and homeostasis of invariant natural killer T cells (2020)
  • Author(s): Kashiwakura Jun-ichi、Saitoh Kodai、Ihara Takeru、Sasaki Yuto、Kagohashi Kota、Enohara Shiyo、Morioka Yuka、Watarai Hiroshi、Muromoto Ryuta、Kitai Yuichi、Iwabuchi Kazuya、Oritani Kenji、Matsuda Tadashi
  • Journal Title: PLOS ONE Volume: 15 Issue: 11 Pages: e0241440-e0241440
  • DOI: 10.1371/journal.pone.0241440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Generation of iNKT cells from iPS cells suitable for cancer immunotherapy (2020)
  • Author(s): Hiroshi Watarai
  • Organizer: International Online Conference on RECENT ADVANCES IN IMMUNOLOGY 2020
  • Int'l Joint Research / Invited