Roles of OX40 and IL-7 in homeostasis of memory T cells

• Project/Area Number: 24390118
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: ISHII NAOTO 東北大学, 医学(系)研究科(研究院), 教授 (60291267)
• Co-Investigator(Kenkyū-buntansha): SO Takanori 東北大学, 大学院医学系研究科, 准教授 (60294964)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 免疫学 / T細胞 / 恒常性維持 / 免疫記憶 / Th17 / 記憶T細胞 / 腸管粘膜免疫 / Th17細胞

Outline of Final Research Achievements

T-cell homeostasis preserves the numbers, the diversity and functional competence of different T cell subsets that are required for adaptive immunity. It is not clear how memory CD4+ T cell subsets are maintained in the periphery and what factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE-labeled CD4+ effector memory T (TEM) cells were transferred into syngeneic C57BL/6 mice, and the systemic cell proliferative responses were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of TEM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL-7. The OX40-dependent fast proliferation preferentially expanded IL-17-producing helper T cells (Th17 cells). Together, both OX40 and IL-7 signals are required during homeostasis of TEM cells, and the synergistic signals may be critical for the expansion of Th17 cells.

Research Products

• [Journal Article] OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy. (2015)
  • Author(s): Shibahara I, Saito R, Zahng R, Chonan M, Kanamori M, Sonoda Y, Kumabe T, Kanehira M, Kikuchi T, So T, Watanabe T, Takahashi H, Iwabuchi E, Tanaka Y, Shibahara Y, Sasano H, Ishii N, and Tominaga T
  • Journal Title: Mol. Cancer Volume: 14 Pages: 41-53
  • NAID: 120006847260
  • Peer Reviewed
• [Journal Article] Fluorescently activated cell sorting followed by microarray profiling of helper T cell subtypes from human peripheral blood. (2014)
  • Author(s): Ono C, Yu Z, Kasahara Y, Kikuchi Y, Ishii N, Tomita H
  • Journal Title: Plos One Volume: 9 Issue: 11 Pages: e111405-e111405
  • DOI: 10.1371/journal.pone.0111405
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. (2014)
  • Author(s): Tsuyoshi Fujita, Benjamin J. Burwitz, Glen M. Chew, Jason S. Reed, Reesab Patahk, Elizabeth Seger, Kiera L. Clayton, James M. Rini, Mario A. Ostrowski, Naoto Ishii, Marcelo J. Kuroda, Scott G. Hansen, Jonah B. Sacha and Lishomwa C. Ndhlovu
  • Journal Title: The Journal of Immunology Volume: 193 Issue: 11 Pages: 5576-83
  • DOI: 10.4049/jimmunol.1400961
  • Peer Reviewed
• [Journal Article] OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4+ T cells. (2014)
  • Author(s): Yamaki S, Ine, S, Kawabe T, Okuyama Y, Suzuki N, Soroosh P, Mousavi SF, Nagashima H, Sun S-L, So T, Sasaki T, Harigae H, Sugamura K, Kudo H, Wada M, Nio M, and Ishii N.
  • Journal Title: European Journal of Immunology Volume: 44 Issue: 10 Pages: 3015-3025
  • DOI: 10.1002/eji.201444701
  • Peer Reviewed
• [Journal Article] Activation of Notch1 promotes development of human CD8+ single positive T cells in humanized mice. (2014)
  • Author(s): Haji Y, Suzuki M, Moriya K, So T, Hozumi K, Mizuma M, Unno M, and Ishii N.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 447 Issue: 2 Pages: 346-351
  • DOI: 10.1016/j.bbrc.2014.04.003
  • Peer Reviewed
• [Journal Article] TNF receptor-associated factor 5 limits inflammatory CD4+ T cell differentiation by antagonizing IL-6-receptor signaling. (2014)
  • Author(s): Nagashima H, Okuyama Y, Asao A, Kawabe T, Yamaki S, Nakano H, Croft M, Ishii N, and So T
  • Journal Title: Nature Immunology Volume: 15 Issue: 5 Pages: 449-456
  • DOI: 10.1038/ni.2863
  • Peer Reviewed
• [Journal Article] OX40 ligand regulates splenic CD8- dendritic cell-induced Th2 responses in vivo. (2014)
  • Author(s): Kamachi F, Harada N, Usui Y, Sakanishi T, Ishii N, Okumura K, Miyake S, Akiba H
  • Journal Title: Biochem Biophys Res Commun Volume: 444 Issue: 2 Pages: 235-240
  • DOI: 10.1016/j.bbrc.2014.01.060
  • Peer Reviewed
• [Journal Article] Activation of Notch1 promotes development of human CD8+ single positive T cells in humanized mice (2014)
  • Author(s): Haji Y., Suzuki M, Moriya K, So T, Hozumi K, Mizuma M, Unno M, and Ishii N
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Homeostatic proliferation of naive CD4^+ T cells in mesenteric lymph no des generates gut-tropic Th17 cells. (2013)
  • Author(s): Takeshi Kawabe, et al
  • Journal Title: J. Immunol. Volume: 190(印刷中) Issue: 11 Pages: 15788-5798
  • DOI: 10.4049/jimmunol.1203111
  • Peer Reviewed
• [Journal Article] Y-chromosome-linked B- and NK-cell deficiency in mice (2013)
  • Author(s): Sun SL, Horino S, Itoh-Nakadai A, Kawabe T, Asao A, Takahashi T, So T, Funayama R, Kondo M, Saitsu H, Matumoto N, Nakayama K, and Ishii N
  • Journal Title: J. Immunol. Volume: 190 Issue: 12 Pages: 6209-6220
  • DOI: 10.4049/jimmunol.1300303
  • Peer Reviewed
• [Journal Article] A smoll molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration. (2013)
  • Author(s): Ichimura A, Matsumoto S, Suzuki S, Dan T, Yamaki S, Sato Y, Kiyomoto H, Ishii N, Okada K, Matsuo O, Hou FF, Vaughan DE, van Ypersele de Strihou S, Miyata T.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 33 Issue: 5 Pages: 935-942
  • DOI: 10.1161/atvbaha.113.301224
  • Peer Reviewed
• [Journal Article] Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/γc^<null> mouse (2012)
  • Author(s): Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K.
  • Journal Title: Int Immunol Volume: 24 Issue: 4 Pages: 243-52
  • DOI: 10.1093/intimm/dxs045
  • Peer Reviewed
• [Journal Article] Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells. (2012)
  • Author(s): Wong WF, Tazawa R, （15名略）Nakata K, Takai T, Satake M.
  • Journal Title: J Immunol. Volume: 188(11) Issue: 11 Pages: 5408-5420
  • DOI: 10.4049/jimmunol.1102991
  • Peer Reviewed
• [Journal Article] Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice (2012)
  • Author(s): Moriya K, Suzuki M, Watanabe Y, Takahashi T, Aoki Y, Uchiyama T, Kumaki S, Sasahara Y, Minegishi M, Kure S, Tsuchiya S, Sugamura K, and Ishii N.
  • Journal Title: PLoS ONE Volume: 7(6) Issue: 6 Pages: e37892-e37892
  • DOI: 10.1371/journal.pone.0037892
  • Peer Reviewed
• [Journal Article] Potential utility of eGFP-expressing NOG mice (NOG-EGFP) as a high purity cancer sampling system (2012)
  • Author(s): Shima K, et al
  • Journal Title: J Exp Clin Cancer Res Volume: 31 Issue: 1 Pages: 55-61
  • DOI: 10.1186/1756-9966-31-55
  • URL: http://www.jeccr.com/content/31/1/55
  • Peer Reviewed
• [Presentation] OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4+ T cells (2014)
  • Author(s): 奥山祐子、山木聡史、河部剛史、石井直人
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都市・国立京都国際会館
  • Year and Date: 2014-12-10
• [Presentation] Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques (2014)
  • Author(s): 藤田剛、石井直人、Ndhlovu LC
  • Organizer: 32nd Nonhuman Primate Models for AIDS
  • Place of Presentation: USA, Portland
  • Year and Date: 2014-11-13
• [Presentation] TRAF5 controls of Th17 development by antagonizing IL-6-receptor signaling (2014)
  • Author(s): 長島宏行、石井直人、宗孝紀
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都市・国立京都国際会館
  • Year and Date: 2014-11-10
• [Presentation] Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques (2014)
  • Author(s): 藤田剛、石井直人、Ndhlovu LC
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都市・国立京都国際会館
  • Year and Date: 2014-11-10
• [Presentation] Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques (2014)
  • Author(s): 藤田剛、石井直人、Ndhlovu LC
  • Organizer: NIH-Japan-JSPS symposium 2014
  • Place of Presentation: USA, Bethesda
  • Year and Date: 2014-10-24
• [Presentation] A novel molecular function of TRAF5 in CD4 T cell lineage commitment (2014)
  • Author(s): 宗孝紀、石井直人
  • Organizer: The 2nd symposium of international immunological memory and vaccine forum
  • Place of Presentation: USA, San Diego
  • Year and Date: 2014-08-25
• [Presentation] TNF receptor-associated factor 5 inhibits Th17 differentiation by antagonizong IL-6-receptor signaling (2014)
  • Author(s): 長島宏行、石井直人、宗孝紀
  • Organizer: The 2nd symposium of international immunological memory and vaccine forum
  • Place of Presentation: USA, San Diego
  • Year and Date: 2014-08-25
• [Presentation] TRAF5はIL-6シグナルを制御することでTh17分化を抑制する (2014)
  • Author(s): 長島宏行、奥山祐子、浅尾敦子、河部剛史、山木聡史、中野裕康、Michael Croft、石井直人、宗孝紀
  • Organizer: 第68回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市・片平さくホール
  • Year and Date: 2014-08-23
• [Presentation] Tim-3を標的とした動物モデルの開発 (2014)
  • Author(s): 藤田剛、石井直人、Ndhlovu LC
  • Organizer: 第68回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市・片平さくホール
  • Year and Date: 2014-08-23
• [Presentation] マクロファージ機能におけるL-アルギニンの効果 (2014)
  • Author(s): 浅尾敦子、宗孝紀、Ndhlovu LC、浅尾裕信、菅村和夫、石井直人
  • Organizer: 第68回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市・片平さくホール
  • Year and Date: 2014-08-23
• [Presentation] Homeostatic proliferation occurs in mesenteric lymph nodes generates gut-tropic Th17 cells. (2013)
  • Author(s): Takeshi Kawabe, et al.
  • Organizer: The 1^<st> Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: Tokyo(招待講演)
  • Year and Date: 2013-01-29
• [Presentation] L-arginine upregulates NO production by macrophages during infection with Leishmania major. (2012)
  • Author(s): Atsuko Asao, ほか
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 2012-12-07
• [Presentation] Homeostatic proliferation occurs in mesenteric lymph nodes and supplies effector memory CD4^+ T cells in the intestine. (2012)
  • Author(s): Takeshi Kawabe, ほか
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 2012-12-07
• [Presentation] TNF receptor-associated factor 5 inhibits Th17 and Tfh differentiation (2012)
  • Author(s): Hiroyuki Nagashima, ほか
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 2012-12-06