Molecular mechanisms of T cell development and functional differentiation in the thymus

• Project/Area Number: 15K08524
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: KIMURA Motoko 千葉大学, 大学院医学研究院, 准教授 (00345018)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 免疫学 / 胸腺 / 胸腺内細胞分化 / 細胞の運命決定 / T細胞 / ヘルパー機能 / TCRシグナル / Thpok / Runx3 / 細胞運命決定 / 胸腺内分化

Outline of Final Research Achievements

Functional lineage-decision either becoming helper lineage cells or killer lineage cells is determined by the duration of TCR signaling that developing T cells receive. Long duration of TCR signaling promotes helper lineage (i.e. CD4T cells); whereas short duration of TCR signaling results in the development of killer cells (i.e. CD8T cells). In this study, we have found that helper function is imposed by TCR signaling independently of Thpok expression so that all positively selected developing cells including MHC-I selected cells once acquire the helper function. However, during CD8T cell development, cytokine-induced Runx3d expression suppresses helper function and endows killer function. In summary, our data reveal that "functional reversal" is occurred during CD8T cell development.

Research Products

• [Int'l Joint Research] 国立衛生研究所 国立がん研究所 (NCI/ NIH)(米国)
• [Journal Article] Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation (2017)
  • Author(s): Kimura Motoko Y.、Hayashizaki Koji、Tokoyoda Koji、Takamura Shiki、Motohashi Shinichiro、Nakayama Toshinori
  • Journal Title: Immunol. Rev. Volume: 278 Issue: 1 Pages: 87-100
  • DOI: 10.1111/imr.12559
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors (2016)
  • Author(s): Kimura, M. Y., Thomas, J., Tai, X., Guinter, T. I., Shinzawa, M., Etzenperger, R., Li, Z., Love, P., Nakayama, T., and Singer, A.
  • Journal Title: Nat. Immunol. Volume: 17 Issue: 12 Pages: 1415-1423
  • DOI: 10.1038/ni.3560
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Myosin light chain 9 and 12 are functional ligands for CD69 that regulate airway inflammation (2016)
  • Author(s): Hayashizaki, K., Kimura, M. Y., Tokoyoda, K., Hosokawa, H., Shinoda, K., Hirahara, K., Ichikawa, T., Onodera, A., Hanazawa, A., Iwamura, C., Kakuta, J., Muramoto, K., Motohashi, S., Tumes, D. J., Iinuma, T., Yamamoto, H., Ikehara, Y., Okamoto, Y., and Nakayama, T.
  • Journal Title: Sci. Immunol. Volume: 1 Issue: 3
  • DOI: 10.1126/sciimmunol.aaf9154
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Methylation of Gata3 at Arg261 regulates transactivation of the Il5 gene in T helper 2 cells (2015)
  • Author(s): Hosokawa, H., Kato, M., Tohyama, H., Tamaki, Y., Endo, Y., Kimura, M. Y., Tumes, D. J., Motohashi, S., Matsumoto, M., Nakayama, K. I., Tanaka, T., and Nakayama, T.
  • Journal Title: J Biol Chem Volume: in press Issue: 21 Pages: 13095-13103
  • DOI: 10.1074/jbc.m114.621524
  • Peer Reviewed / Open Access
• [Journal Article] Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function (2015)
  • Author(s): Pobezinsky, L.A., Etzensperger, R., Jeurling, S., Alag, A., Kadakia, T., McCaughtry, T.M., Kimura, M.Y., Sharrow, S.O., Guinter, T.I., Feigenbaum, L. and Singer, A.
  • Journal Title: Nature Immunology Volume: 16 Issue: 5 Pages: 517-524
  • DOI: 10.1038/ni.3146
  • Peer Reviewed / Int'l Joint Research
• [Presentation] CD69-Myl9 system regulates pathogenesis of inflammatory disorders (2018)
  • Author(s): Kimura M.Y., Hayashizaki K., Nakayama T.
  • Organizer: The 2nd Chiba University-UC San Diego Symposium "Mucosal Immunology, Allergy and Vaccine"
  • Int'l Joint Research / Invited
• [Presentation] Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation. (2017)
  • Author(s): Hayashizaki, K., Kimura, M.Y., Igi, A., and Nakayama, T.
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 京都大学医学部・芝蘭会館（京都府京都市）
  • Year and Date: 2017-03-17
  • Int'l Joint Research
• [Presentation] Myosin light chain 9 and 12 are functional ligands for CD69 that regulate airway inflammation (2017)
  • Author(s): Kimura M.Y., Hayashizaki K., Nakayama T.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society 2017
  • Int'l Joint Research / Invited
• [Presentation] Timing and duration of MHC-I positive selection and CD8 lineage choice in the thymus. (2016)
  • Author(s): Kimura M.Y.
  • Organizer: NIH Thymus Symposium
  • Place of Presentation: NIH, Bethesda, USA
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] Timing and duration of MHC-I positive selection signals in the thymus reveal a novel compensatory signaling mechanism that prevents lineage fate errors. (2016)
  • Author(s): Kimura, M.Y., Nakayama, T., and Singer, A.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] Roles of IL-2 on Th9 cell differentiation (2015)
  • Author(s): Sarkar, H. M., Yagi, R., Nakajima, T., Kimura, M., Nakayama, T., and Zhu, J.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市)
  • Year and Date: 2015-11-18
• [Presentation] Molecular basis for acquisition of helper function during thymocyte development (2015)
  • Author(s): Motoko Y. Kimura, Toshinori Nakayama and Alfred Singer
  • Organizer: 第25回 Kyoto T Cell Conference
  • Place of Presentation: 京都大学芝蘭会館 (京都府京都市）
  • Year and Date: 2015-05-16
• [Presentation] Strong TCR signaling prolongs lineage uncertainty during MHC-I specific positive selection (2015)
  • Author(s): Kimura, M., Nakayama, T., and Singer, A.
  • Organizer: Immunology 2015 AAI Annual Meeting
  • Place of Presentation: New Orleans (U.S.A.)
  • Year and Date: 2015-05-08
  • Int'l Joint Research
• [Presentation] Molecular basis for acquisition of helper function during thymocyte development (2015)
  • Author(s): Motoko Y. Kimura, Miho Shinzawa, Ruth Etzensperger, Ryoji Yagi, Koji Hayashizaki, Akemi Igi, Toshinori Nakayama and Alfred Singer
  • Organizer: Venice Thymus Meeting 2015
  • Place of Presentation: Venice (Italy)
  • Year and Date: 2015-04-09
  • Int'l Joint Research
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/
• [Remarks] 千葉大学大学院医学研究院免疫発生学ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/index.html