Immunological tolerance regulated by the interaction between T cell and antigen-presenting cell

• Project/Area Number: 15390155
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: ISHII Naoto Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (60291267)
• Co-Investigator(Kenkyū-buntansha): ASAO Hironobu Yamagata University, Faculty of Medicine, Professor, 医学部, 教授 (80250744)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥15,400,000 (Direct Cost: ¥15,400,000); Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000); Fiscal Year 2003: ¥9,500,000 (Direct Cost: ¥9,500,000)
• Keywords: Immunological tolerance / CD4^+ T cell / Antigen presenting cell / regulatory T cells / T-cell costimulatory signals / T細胞 / 自己免疫疾患 / OX40リガンド

Research Abstract

The presence of OX40^+ lymphocytes and OX40 ligand^+ (OX40L)^+ cells at the sites of inflammation in T cell-mediated disorders, such as autoimmunity, allergic and infectious diseases, and GVHD is well documented. These observations suggest important roles for OX40-OX40L interactions in immune disorders. CD25^+CD4^+ regulatory T (Treg) cells suppress autoinununity by controlling peripheral self-reactive T cell activation. Recently, several reports have revealed that OX40 is preferentially expressed on Treg cells in terms of mRNA and protein expression in mice. Thus we examined whether OX40-OX40L interaction may control Treg cell function that are essential for preventing autoimmunity.
We found by using OX40L-deificient mice and mice overexpressing OX40L that CD25^-CD4^+ T cells became insensitive to Treg-mediated suppression when they were exposed to OX40L-expressing cells, or when they were treated with an agonistic OX40-specific monoclonal antibody. OX40 signaling could also abrogate the disease-preventing activity of Treg cells in an experimental model of inflammatory bowel disease using RAG2-deficient mice that expressed different levels of OX40L. Thus, these data show that OX40 signals can oppose Treg-mediated suppression when they are delivered directly to antigen-engaged naive T cells. Taken together, OX40 signaling directly control Treg-cell-mediated immune suppression.

Research Products

• [Journal Article] Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. (2005)
  • Author(s): Wang, X., Ishii, N.ほか
  • Journal Title: Nat.Genet 37 Pages: 365-372
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hrs, a mammalian master molecule in vesicular transport and protein-sorting, suppresses the degradation of ESCRT proteins STAM1 and STAM2. (2005)
  • Author(s): Kobayashi, H., Ishii, N.ほか
  • Journal Title: J.Biol.Chem. 280 Pages: 10468-10477
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. (2005)
  • Author(s): Wang, X., Ria, M., Kelmenson, P.M., Eriksson, P., Higgins, D.C., Samnegard, A., Petros C, Rollins, J., Bennet, A.M., Wiman, B., de Faire, U., Wennberg, C., Olsson, P.G., Ishii, N., Sugamura, K., Hamsten, A., Forsman-Semb, K., Lagercrantz, J., Paigen, B.
  • Journal Title: Nat.Genet. 37 Pages: 365-372
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hrs, a mammalian master molecule in vesicular transport and protein-sorting, suppresses the degradation of ESCRT proteins STAM1 and STAM2. (2005)
  • Author(s): Kobayashi, H., Tanaka, N., Asao, H., Miura, S., Kyuuma, M., Semura, K., Ishii, N., Sugamura K.
  • Journal Title: J.Biol.Chem. 280 Pages: 10468-10477
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. (2005)
  • Author(s): Wang, X., Ishii, N.ほか
  • Journal Title: Nat.Genet (印刷中)
• [Journal Article] Distinct roles for the OX40-OX40L interaction regulatory and non-regulatory T cells. (2004)
  • Author(s): Takeda, I., Ishii, N.ほか
  • Journal Title: J.Immunol 172 Pages: 3580-3589
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances anti-tumor immunity of tumor-bearing hosts. (2004)
  • Author(s): Andrini, S., Ishii, N.ほか
  • Journal Title: Cancer Res. 64 Pages: 3281-3287
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic targeting of the effector T cell costimulatory molecule OX40 (2004)
  • Author(s): Sugamura, K., Ishii, N., Weinberg, A.D
  • Journal Title: Nat.Rev.Immunol. 4 Pages: 420-431
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TNFα is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. (2004)
  • Author(s): Horai, R., Ishii, N.ほか
  • Journal Title: J.Clin.Invest. 114 Pages: 1603-1611
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expanding role of T-cell costimulators in regulatory T-cellfunction : recent advances in accessory molecules expressed onboth regulatory and non-regulatory T cells. (2004)
  • Author(s): Ndhlovu, L.C., Ishii, N.ほか
  • Journal Title: Crit.Rev.Immunol 24 Pages: 251-266
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential role of OX40L on B cell in persistent alloantibody production following repeated alloimmunizations. (2004)
  • Author(s): Kato, H., Ishii, N.ほか
  • Journal Title: J.Clin.Immunol. 24 Pages: 237-248
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. (2004)
  • Author(s): Feng, J., Ishii, N.ほか
  • Journal Title: Multiple Sclerosis 10 Pages: 494-498
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct roles for the OX40-OX40L interaction in regulatory and non-regulatory T cells. (2004)
  • Author(s): Takeda, I., Ine, S., Killeen, N., Ndhlovu, L.C., Murata, K., Satomi, S., Sugamura, K., Ishii, N.
  • Journal Title: J.Immunol. 172 Pages: 3580-3589
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances anti-tumor immunity of tumor-bearing hosts. (2004)
  • Author(s): Andarini, S., Kikuch, T., Nukiwa, M., Pradono, P., Suzuki, T., Ohkouchi, S., Inoue, A., Maemondo, M., Ishii, N., Saijo, Y., Sugamura, K., Nukiwa, T.
  • Journal Title: Cancer Res. 64 Pages: 3281-3287
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Essential role of OX40L on B cells in persistent alloantibody production following repeated alloimmunizations (2004)
  • Author(s): Kato, H., Kojima, H., Ishii, N., Hase, H., Imai, Y., Fujibayashi, T., Sugamura, K., Kobata, T.
  • Journal Title: J.Clin.Immunol. 24 Pages: 237-248
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. (2004)
  • Author(s): Feng, J., Misu, T., Fujihara, K., Sakoda, S., Nakatsuji, Y., Fukaura, H., Kikuchi, S., Tashiro, K., Suzumura, A., Ishii, N., Sugamura, K., Nakashima, I., Itoyama, Y.
  • Journal Title: Multiple Sclerosis 10 Pages: 494-498
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic targeting of the effector T cell costimulatoiy molecule OX40. (2004)
  • Author(s): Sugamura, K., Ishii, N., Weinberg, A.D.
  • Journal Title: Nat.Rev.Immunol. 4 Pages: 420-431
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TNFα is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. (2004)
  • Author(s): Horai, R., Nakajima, A., Habiro, K., Kotani, M., Nakae, S., Matsuki, T, Nambu, A., Saijo, S., Kotaki, H., Sudo, K., Okahara, A., Tanioka, H., Ikuse, T., Ishii, N., Schwartzberg, P.L., Abe, R., Iwakura, Y.
  • Journal Title: J.Clin.Invest. 114 Pages: 1603-1611
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expanding role of T-cell costimulators in regulatory T-cellfunction : recent advances in accessory molecules expressed onboth regulatory and non-regulatory T cells. (2004)
  • Author(s): Ndhlovu, L.C., Takeda, I., Sugamura, K., Ishii, N.
  • Journal Title: Crit.Rev.Immunol. 24 Pages: 251-266
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances anti-tumor immunity of tumor-bearing hosts. (2004)
  • Author(s): Andarini, S., Ishii, N.ほか
  • Journal Title: Cancer Res. 64 Pages: 3281-3287
• [Journal Article] Critical role of OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma. (2003)
  • Author(s): Hoshino, A., Ishii, N.ほか
  • Journal Title: Eur.J.Immunol. 33 Pages: 861-869
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. (2003)
  • Author(s): Kikuchi, K., Ishii, N.ほか
  • Journal Title: Biochem.Biophys.Res.Commun 306 Pages: 637-643
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] OX40(CD134)and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. (2003)
  • Author(s): Ishii, N., Ndhlovu, L.C.ほか
  • Journal Title: Eur.J.Immunol. 33 Pages: 2372-2381
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation. (2003)
  • Author(s): Kanazawa, C., Ishii, N.ほか
  • Journal Title: Biochem.Biophys.Res.Commun. 309 Pages: 848-856
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma. (2003)
  • Author(s): Hoshino, A., Tanaka, Y., Akiba, H., Asakura, Y., Mita, Y., Sakurai, T., Takaoka, A., Nakaike, S., Ishii, N., Sugamura, K., Yagita, H., Okumura, K.
  • Journal Title: Eur.J.Immunol. 33 Pages: 861-869
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. (2003)
  • Author(s): Kikuchi, K., Ishii, N., Asao, H., Sugamura, K.
  • Journal Title: Biochem.Biophys.Res.Commun. 306 Pages: 637-643
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. (2003)
  • Author(s): Ishii, N., Ndhlovu, L.C., Murata, K., Sato, T., Kamanaka, M., Sugamura, K.
  • Journal Title: Eur.J.Immunol. 33 Pages: 2372-2381
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation. (2003)
  • Author(s): Kanazawa, C., Morita, E., Yamada, M., Ishii, N., Miura, S., Asao, H., Yoshimori, T., Sugamura, K.
  • Journal Title: Biochem.Biophys.Res.Commun. 309 Pages: 848-856
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kato, H., Kojima, H., Ishii, N., Hase, H., Imai, Y., Fujibayashi, T., Sugamura, K., Kobata, T.: "Essential role of OX40L on B cells in persistent alloantibody production following repeated alloimmunizations"J.Clin.Immunol.. (印刷中). (2004)
• [Publications] Andarini, S., Kikuch, T., Nukiwa, M., Pradono, P., Suzuki, T., Ohkouchi, S., Inoue, A., Maemondo, M., Ishii, N., Saijo, Y., Sugamura, K., Nukiwa, T.: "Adenovirus Vector-Mediated in vivo gene transfer of OX40 ligand to tumor cells enhances anti-tumor immunity of tumor-bearing hosts"Cancer Res.. (印刷中). (2004)
• [Publications] Takeda, I., Ine, S., Killeen, N., Ndhlovu, L.C., Murata, K., Satomi, S., Sugamura, K., Ishii, N.: "Distinct roles for the OX40-OX40L interaction in regulatory and non-regulatory T cells"J.Immunol.. 172. 3580-3589 (2004)
• [Publications] Kanazawa, C., Morita, E., Yamada, M., Ishii, N., Miura, S., Asao, H., Yoshimori, T., Sugamura, K.: "Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation"Biochem.Biophys.Res.Commun.. 309. 848-856 (2003)
• [Publications] Ishii, N., Ndhlovu, L.C., Murata, K., Sato, T., Kamanaka, M., Sugamura, K.: "OX40(CD134)and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses"Eur.J.Immunol.. 33. 2372-2381 (2003)
• [Publications] Kikuchi, K., Ishii, N., Asao, H., Sugamura, K.: "Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif"Biochem.Biophys.Res.Commun.. 306. 637-643 (2003)