Control of dynamics and function of T cells by glucocorticoids via IL-7 receptor expression

• Project/Area Number: 16K15288
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: Ikuta Koichi 京都大学, ウイルス・再生医科学研究所, 教授 (90193177)
• Co-Investigator(Kenkyū-buntansha): 谷一 靖江 京都大学, 医学研究科, 助教 (50432331)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ステロイド / T細胞 / IL-7 / 概日リズム / 内分泌系 / 適応免疫 / 糖質コルチコイド / 免疫学 / 内科 / 感染症 / 生理学

Outline of Final Research Achievements

Glucocorticoids are a group of steroid hormones with strong anti-inflammatory and immunosuppressive effects. However, the physiological function of glucocorticoids in the immune system remains largely unclear. We found that the glucocorticoid receptor induces IL-7 receptor (IL-7R) expression in T cells by binding to the enhancer of the IL-7R locus, and that the induction followed diurnal rhythm of glucocorticoid concentration. The diurnal expression of IL-7R supported T cell survival and triggered T cell redistribution between lymph nodes, spleen, Peyer’s patches and blood by inducing the chemokine receptor, CXCR4. CXCR4 induction triggered T cell migration to spleen and Peyer’s patches. Consequently, T cell accumulation in spleen promoted immune responses against systemic bacterial infection and antigen administration. Our study reveals the immunoenhancing role of glucocorticoids, and provides insights how the immune function is controlled by the diurnal rhythm.

Research Products

• [Int'l Joint Research] Kantonsspital St. Gallen/Heinrich Heine University/University of Bern, Bern(スイス、ドイツ)
• [Int'l Joint Research] Yale University/German Cancer Research Center/University of Leuven(米国、ドイツ、ベルギー)
• [Journal Article] Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4 (2018)
  • Author(s): Shimba A, Cui G, Tani-Ichi S, Ogawa M, Abe S, Okazaki F, Kitano S, Miyachi H, Yamada H, Hara T, Yoshikai Y, Nagasawa T, Schütz G, Ikuta K.
  • Journal Title: Immunity Volume: 48 Issue: 2 Pages: 286-298
  • DOI: 10.1016/j.immuni.2018.01.004
  • NAID: 120006401712
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing γδ T cells (2017)
  • Author(s): Nakamizo Satoshi、Honda Tetsuya、Adachi Akimasa、Nagatake Takahiro、Kunisawa Jun、Kitoh Akihiko、Otsuka Atsushi、Dainichi Teruki、Nomura Takashi、Ginhoux Florent、Ikuta Koichi、Egawa Gyohei、Kabashima Kenji
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 999-999
  • DOI: 10.1038/s41598-017-14292-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sepsis-induced osteoblast ablation causes immunodeficiency (2016)
  • Author(s): Terashima, A., Okamoto, K., Nakashima, T., Akira, S., Ikuta, K. and Takayanagi, H.
  • Journal Title: Immunity Volume: 44 Issue: 6 Pages: 1434-1443
  • DOI: 10.1016/j.immuni.2016.05.012
  • Peer Reviewed / Open Access
• [Journal Article] Thy-1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation (2016)
  • Author(s): Shinoda, K., Hirahara, K., Iinuma, T., Ichikawa, T., Suzuki, A. S., Sugaya, K., Tumes, D. J., Yamamoto, H., Hara, T., Tani-ichi, S., Ikuta, K., Okamoto, Y., and Nakayama, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 113 Issue: 20
  • DOI: 10.1073/pnas.1512600113
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblastic reticular cells regulate intestinal inflammation through IL-15-mediated control of group 1 ILCs (2016)
  • Author(s): Gil-Cruz, C., Perez-Shibayama, C., Onder, L., Chai, Q., Cupovic, J., Cheng, H., Novkovic, M., Lang, P. A., Geuking, M. B., McCoy, K. D., Abe, S., Cui, G., Ikuta, K., Scandella, E., and Ludewig, B.
  • Journal Title: Nat. Immunol. Volume: 17 Issue: 12 Pages: 1388-1396
  • DOI: 10.1038/ni.3566
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hematopoietic stem cell niches produce lineage-instructive signals to control multipotent progenitor differentiation (2016)
  • Author(s): Gomes, A. C., Hara, T., Lim, V. Y., Herndler-Brandstetter, D., Nevius, E., Sugiyama, T., Tani-ichi, S., Schlenner, S., Richie, E., Rodewald, H., Flavell, R. A., Nagasawa, T., Ikuta, K., and Pereira, J. P.
  • Journal Title: Immunity Volume: 45 Issue: 6 Pages: 1219-1231
  • DOI: 10.1016/j.immuni.2016.11.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Glucocorticoids drive circadian changes in T-cell homing and response via IL-7 receptor (2017)
  • Author(s): Shimba, A., and Ikuta, K.
  • Organizer: Immunology 2017 (AAI)
  • Int'l Joint Research
• [Presentation] IL-7Rα signaling upregulates growth hormone signaling-related gene in naive T cells (2017)
  • Author(s): Tani-ichi, S., and Ikuta, K.
  • Organizer: Keystone Symposium: Integrating Metabolism and Immunity
  • Int'l Joint Research
• [Presentation] Osteoblasts mediate immunosuppression during sepsis by regulating lymphopoiesis (2017)
  • Author(s): Terashima, A., Okamoto, K., Nakashima, T., Ikuta, K., and Takayanagi, H.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] グルココルチコイドはIL-7受容体の発現を介してT細胞の体内分布および活性化の日内変動を制御する (2017)
  • Author(s): 岡崎史恵、榛葉旭恒、崔広為、生田宏一
  • Organizer: ConBio2017（生命科学系学会合同年次大会）
• [Presentation] Glucocorticoids drive diurnal changes in distribution and response of T cells via IL-7 receptor expression (2017)
  • Author(s): Shimba, A., Cui, G., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Competition between STAT5 and PI3K of the IL-7R modulates T cell and type 2 ILC development in vivo (2017)
  • Author(s): Cui, G., Shimba, A., Zhu, Y., Tani-ichi, S., Hara, T., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Exploring the signals upregulating IL-7Rα expression via NFκB activation in T cells (2017)
  • Author(s): Tani-ichi, S., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Regulation of IL-7 receptor expression by a proximal enhancer (2017)
  • Author(s): 榛葉旭恒、崔広為、谷一靖江、原崇裕、生田宏一
  • Organizer: KTCC 2017
  • Place of Presentation: 芝蘭会館、京都
  • Int'l Joint Research
• [Presentation] Role of glucocorticoids in T cell homeostasis and T cell response (2016)
  • Author(s): 榛葉旭恒、崔広為、阿部真也、朱媛博、向平妃沙、谷一靖江、原崇裕、生田宏一
  • Organizer: The 23rd East Asia Joint Symposium
  • Place of Presentation: 台北、台湾
  • Int'l Joint Research
• [Remarks] ステロイドが免疫力を高める？！ －免疫の新たな昼夜サイクルを解明 －
  • URL: http://www.infront.kyoto-u.ac.jp/achievements/post-2986/
• [Remarks] ステロイドが免疫力を高める －免疫の新たな昼夜サイクルを解明－
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2017/180124_1.html
• [Remarks] 多能性造血前駆細胞からリンパ球までの分化を方向付ける骨髄ニッチの同定
  • URL: http://www.infront.kyoto-u.ac.jp/achievements/post-1160/