Molecular basis of the function and generation of Foxp3-expressing regulatory T cells

2012 Fiscal Year Final Research Report

• Project/Area Number: 20002007
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University (2011-2012); Kyoto University (2008-2010)
• Principal Investigator: SAKAGUCHI Shimon 大阪大学, 免疫学フロンティア研究センター, 教授 (30280770)
• Co-Investigator(Kenkyū-buntansha): OHKURA Naganari 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (20300949) ; NISHIKAWA Hiroyoshi 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (10444431) ; YAMAGUCHI Tomoyuki 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (80402791) ; ITO Yoshinaga 京都大学, 再生医科学研究所, 助教 (60614013)
• Co-Investigator(Renkei-kenkyūsha): KONDO Gen 京都大学, 再生医科学研究所, 准教授 (40243258) ; KITABAYASHI Issei 国立がんセンター研究所, 分子腫瘍学部長 (20261175) ; TANIUCHI Ichiro 理化学研究所, 免疫転写制御研究チーム, チームリーダー (20284573)
• Project Period (FY): 2008 – 2012
• Keywords: FOXP3 / 制御性T細胞 / 自己免疫病 / Tリンパ球 / CTLA-4 / 免疫制御

Research Abstract

We have studied the mechanisms of how regulatory T (Treg) cells control immune responses and how their function and lineage stability can be maintained. We showed that several Treg-specific molecules were engaged in the control of antigen-presenting cells and thereby responsible for suppressing immune responses and that Treg-specific epigenetic changes were essential for the stability of Treg function. In addition, we showed that human Tregs were functionally dissected into three subsets and that this classification was instrumental in understanding the pathogenetic mechanisms of immunological diseases.

Research Products

• [Journal Article] Development and Maintenance of Regulatory T cells. (2013)
  • Author(s): Ohkura N, Kitagawa Y, Sakaguchi S.
  • Journal Title: Immunity Volume: 38 Pages: 414-423
• [Journal Article] Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes (2013)
  • Author(s): Hirayama M, Nishikawa H, Nagata Y, Tsuji T, Kato T, Kageyama S, Ueda S, Sugiyama D, Hori S, Sakaguchi S, Ritter G, Old LJ, Gnjatic S, Shiku H.
  • Journal Title: Eur J Immunol
• [Journal Article] T cell receptor stimulation-induced epigenetic changes and foxp3 expression are independent and complementary events required for Treg cell development. (2012)
  • Author(s): Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S.
  • Journal Title: Immunity. Volume: 37 Pages: 785-99
• [Journal Article] Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth (2012)
  • Author(s): Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, Albert J, Sparwasser T, Sakaguchi S, Westendorf AM, Schadendorf D, Buer J, Helfrich I.
  • Journal Title: J Exp Med. Volume: 209 Pages: 2001-16
• [Journal Article] Intracellular tumor-associated antigens represent effective targets for passive immunotherapy. (2012)
  • Author(s): Noguchi, T., Kato, T., Wang, L., Maeda,Y., Ikeda, H., Sato, E., Knuth, A., Gnjatic, S., Ritter, G., Sakaguchi, S., Old, L. J., Shiku, H., and Nishikawa, H
  • Journal Title: Cancer Res. Volume: 72 Pages: 1672-1682
• [Journal Article] Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. (2012)
  • Author(s): Kinoshita M, Kayama H, Kusu T, Yamaguchi T, Kunisawa J, Kiyono H, Sakaguchi S, Takeda K.
  • Journal Title: J Immunol. Volume: 189 Pages: 2869-78
• [Journal Article] Multiple treg suppressive modules and their adaptability. (2012)
  • Author(s): Wing JB, Sakaguchi S
  • Journal Title: Front Immunol. Volume: 3 Pages: 178
• [Journal Article] Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma. (2012)
  • Author(s): Nishikawa, H., Maeda, Y., Ishida, T.,Gnjatic, S., Sato, E., Mori, F.,Sugiyama, D., Ito, A., Fukumori, Y., Utsunomiya, A., Inagaki, H., Old, L. J., Ueda, R., and Sakaguchi, S.
  • Journal Title: Blood. Volume: 119 Pages: 3097-3104
• [Journal Article] T-cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. (2012)
  • Author(s): Sakaguchi, S., Benham, H., Cope,A. P., Thomas, R.
  • Journal Title: Immunol Cell Biol. Volume: 90 Pages: 277-87
• [Journal Article] Re-establishingimmunological self- tolerance in autoimmune disease. (2012)
  • Author(s): Sakaguchi, S., Powrie, F., Ransohoff, R. M.
  • Journal Title: Nat Med. Volume: 18 Pages: 54-58
• [Journal Article] Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match. (2012)
  • Author(s): Ohe, H., Waki, K., Yoshitomi, M., Morimoto, T., Nafady-Hego, H., Satoda,N., Li, Y., Zhao, X., Sakaguchi, S., Uemoto, S., Bishop, G. A., Koshiba, T
  • Journal Title: Transpl Int. Volume: 25 Pages: 97-106
• [Journal Article] Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiation (2012)
  • Author(s): Yoshioka, Y., Ono, M., Osaki, M., Konishi, I., Sakaguchi, S.
  • Journal Title: Eur J Immunol Volume: 42 Pages: 749-759
• [Journal Article] Cell-autonomous and -nonautonomous functions of CTLA-4 for negative control of immune responses (2011)
  • Author(s): Wing, K., Yamaguchi, T., Sakaguchi, S.
  • Journal Title: Trends Immunol. Volume: 32 Pages: 428-43
• [Journal Article] The long-term survival potential of mature T lymphocytes is programmed during development in the thymus. (2011)
  • Author(s): Sinclair, C., Saini, M., van der Loeff, I. S., Sakaguchi, S., Seddon, B
  • Journal Title: Sci Signal. Volume: 4(199) Pages: ra77
• [Journal Article] Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions (2011)
  • Author(s): Yamaguchi, T., Wing, J. B., Sakaguchi, S.
  • Journal Title: Semin Immunol. Volume: 23 Pages: 424-430
• [Journal Article] innate immunity and autoimmune arthritis: interplay of gene and environment. (2011)
  • Author(s): Sakaguchi, S., Tanaka, S., Tanaka,A., Ito, Y., Maeda, S., Sakaguchi, N., Hashimoto, M. Thymus
  • Journal Title: FEBS Lett. Volume: 585 Pages: 3633-3639
• [Journal Article] FOXP3(+) regulatory T cells: control of FOXP3 expression by pharmacological agents (2011)
  • Author(s): 3633-3639, 2011.18. Ohkura, N., Hamaguchi, M., Sakaguchi, S.
  • Journal Title: Trends Pharmacol. Sci. Volume: 32 Pages: 158-66
• [Journal Article] Minimal but essential doses of immunosuppression: A more realistic approach to improve long-term outcomes for pediatric living-donor liver transplantation (2011)
  • Author(s): Ohe, H., Li, Y., Nafady-Hego, H., Kayo, W., Sakaguchi, S., Wood, K., Calne,R., Uemoto, S., Koshiba, T.
  • Journal Title: Transplantation Volume: 91 Pages: 808-810
• [Journal Article] HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. (2011)
  • Author(s): Satou, Y., Yasunaga, J., Zhao, T., Yoshida, M., Miyazato, P., Takai, K., Shimizu, K., Ohshima, K., Green, P. L., Ohkura, N., Yamaguchi, T., Ono, M., Sakaguchi, S., Matsuoka, M.
  • Journal Title: PLoS Pathog. Volume: 7(2) Pages: e1001274
• [Journal Article] Human FoxP3(+) regulatory T cells in systemic autoimmune diseases (2011)
  • Author(s): Miyara, M., Gorochov, G., Ehrenstein, M., Musset, L., Sakaguchi,S., Amoura, Z.
  • Journal Title: Autoimmun. Rev Volume: 10 Pages: 744-755
• [Journal Article] FoxP3+CD4+ regulatory T cells: their knowns and unknowns. (2011)
  • Author(s): Miyara, M., and Sakaguchi, S
  • Journal Title: Immunol. Cell. Biology. Volume: 89 Pages: 346-351
• [Journal Article] SLAP Deficiency Enhances Number and Function of Tregs Preventing Chronic Autoimmune Arthritis in SKG Mice. (2011)
  • Author(s): Peterson, L. K., Shaw, L. A., Joetham, A., Sakaguchi, S., Gelfand, E. W.,and Dragone, L. L.
  • Journal Title: J. Immunol. Volume: 186 Pages: 1173-1181
• [Journal Article] Stimulation of the glucocorticoid- induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens. (2011)
  • Author(s): Cote, A. L., Zhang, P., O'Sullivan,J. A., Jacobs, V. L., Clemis, C. R., Sakaguchi, S., Guevara-Patino, J. A., and Turk, M. J.
  • Journal Title: J. Immunol. Volume: 186 Pages: 275-283
• [Journal Article] Regulatory T cells: history and perspective. (2011)
  • Author(s): Sakaguchi, S.
  • Journal Title: Methods in Molecular Biology. Volume: 77 Pages: 1-13
• [Journal Article] CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection. (2010)
  • Author(s): Snell, L. M., McPherson, A. J., Lin, G. H., Sakaguchi, S., Pandolfi, P. P., Riccardi, C., and Watts, T. H.
  • Journal Title: J.Immunol. Volume: 185 Pages: 7223-7234
• [Journal Article] Perturbations of both non-regulatory and regulatory FOXP3(+) T cells in patients with malignant melanoma. (2010)
  • Author(s): Fujii, H., Arakawa, A., Kitoh, A., Miyara, M., Kato, M., Kore-Eda, S., Sakaguchi, S., Miyachi, Y., Tanioka, M., and Ono, M.
  • Journal Title: Br. J. Dermatol. Volume: 164 Pages: 1052-1060
• [Journal Article] Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. (2010)
  • Author(s): Mitsui, J., Nishikawa, H., Muraoka, D., Wang, L., Noguchi, T., Sato,E., Kondo, S., Allison, J. P., Sakaguchi,S., Old, L. J., Kato, T., and Shiku, H.
  • Journal Title: Clin. Cancer Res. Volume: 16 Pages: 2781-91
• [Journal Article] Regulatory T cells in tumor immunity (2010)
  • Author(s): Nishikawa, H., and Sakaguchi, S
  • Journal Title: Int. J. Cancer. Volume: 127 Pages: 759-67
• [Journal Article] Regulatory T cells: roles of Tcell erceptor for their development and function. (2010)
  • Author(s): Ohkura, N., and Sakaguchi, S
  • Journal Title: Semin. Immunopathol. Volume: 32 Pages: 95-106
• [Journal Article] FOXP3+ regulatory T cells in the human system. (2010)
  • Author(s): Sakaguchi, S., Miyara, M., Costantino, C. M., and Hafler, D. A.
  • Journal Title: Nat. Rev. Immunol. Volume: 185 Pages: 2295-305
• [Journal Article] Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. (2010)
  • Author(s): Teng, M.W., Swann, J.B., von Scheidt B, Sharkey, J., Zerafa, N., McLaughlin, N., Yamaguchi, T., Sakaguchi, S., Darcy, P.K., and Smyth,M.J.
  • Journal Title: Cancer Res Volume: 70 Pages: 2665-2674
• [Journal Article] Therapeutic Glucocorticoid-Induced TNF Receptor-Mediated Amplification of CD4+ T Cell Responses Enhances Antiparasitic Immunity. (2010)
  • Author(s): Haque, A., Stanley, A. C., Amante,F. H., Rivera, F. D., Zhou, Y., Kuns, R. D., Yardley, V., Sakaguchi, S., Hill, G. R., and Engwerda, C. R
  • Journal Title: J. Immunol. Volume: 184 Pages: 2583-2592
• [Journal Article] Complement drives Th-17 cell differentiation and triggers autoimmune disease. (2010)
  • Author(s): Hashimoto, M., Hirota, K., Yoshitomi, H., Maeda, S., Teradaira, S.,Akizuki, S., Prieto-Martin, P., Nomura, T., Sakaguchi, N., Kohl, J., Heyman, B.,Takahashi, M., Fujita, T., Mimori, T., Sakaguchi, S.
  • Journal Title: J. Exp. Med. Volume: 207 Pages: 1135-43
• [Journal Article] Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. (2010)
  • Author(s): Tanaka, S., Maeda, S., Hashimoto. M., Teradaira, S., Hirota,K., Yoshitomi, H., Katakai, T., Shimizu, A., Nomura, T., Sakaguchi, N., and Sakaguchi, S.
  • Journal Title: J. Immunol. Volume: 185 Pages: 2295-305
• [Journal Article] Regulatory T cells exert checks and balances on self-tolerance and autoimmunity. (2010)
  • Author(s): Wing, K., and Sakaguchi, S.Regulatory T cells exert checks and
  • Journal Title: Nat. Immunol Volume: 11 Pages: 7-13
• [Journal Article] Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. (2009)
  • Author(s): Onodera, T., Jang, M. H., Guo, Z., Yamasaki, M., Hirata, T., Bai, Z., Tsuji,N. M., Nagakubo, D., Yoshie, O., Sakaguchi, S., Takikawa, O., and Miyasaka, M.
  • Journal Title: J. Immunol Volume: 183 Pages: 5608-5614
• [Journal Article] Regulatory T cells: how do they suppress immune responses? (2009)
  • Author(s): Sakaguchi, S., Wing, K., Onishi,Y.
  • Journal Title: Int. Immunol Volume: 21 Pages: 1105-11
• [Journal Article] Indispensable role of Runx1/Cbf・complexes for in vivo suppressive function of FoxP3+regulatory T cells (2009)
  • Author(s): Kitoh, A., Ono, M., Naoe, Y., Ohkura, N., Yamaguchi, T, Yaguchi, H., Kitabayashi, I., Tsukada, T., Nomura, T., Miyachi,Y., Taniuchi, I., and Sakaguchi, S.
  • Journal Title: Immunity. Volume: 31 Pages: 609-620
• [Journal Article] Dynamics of peripheral tolerance and immune regulation mediated by Treg (2009)
  • Author(s): Sakaguchi, S., Wing, K., and Yamaguchi, T.
  • Journal Title: Eur. J. Immunol Volume: 39 Pages: 2331-6
• [Journal Article] CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2 (2009)
  • Author(s): Okamura, T., Fujio, K., Shibuya,M., Sumitomo, S., Shoda, H., Sakaguchi,S., and Yamamoto, K.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 106 Pages: 13974-9
• [Journal Article] M., Wing, K., and Sakaguchi, S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. (2009)
  • Author(s): Miyara, M., Wing, K., and Sakaguchi, S.
  • Journal Title: J Allergy Clin Immunol Volume: 123 Pages: 749-55
• [Journal Article] Functional delineation and differentiation dynamics of human CD4(+) T cells expressing the FoxP3 transcription factor. (2009)
  • Author(s): Miyara, M., Shima, T., Kitoh, A., Yoshioka, Y., Niwa, A., Taflin, C., Heike, T., Valeyre, D., Mathian, A., Nakahata, T., Yamaguchi T., Nomura, T., Wing, K., Ono, M., Amoura, Z., Gorochov, G., and Sakaguchi, S.
  • Journal Title: Immunity Volume: 30 Pages: 899-911
• [Journal Article] Differential control of alloantigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance. (2009)
  • Author(s): Nagahama, K., Fehervari, Z., Oida, T., Ogawa, O., and Sakaguchi, S.
  • Journal Title: Int.Immunol. Volume: 21 Pages: 379-391
• [Journal Article] Requirement of protocol biopsy before and after complete cessation of immunosuppression following liver transplantation. (2009)
  • Author(s): Yoshitomi, M., Koshiba, T., Haga, H., Li, Y., Zhao, X., Cheng, D., Miyagawa, A., Sakashita, H., Tsuruyama T., Ueda, M., Wood, K., Sakaguchi S., Manabe, T., Tanaka, K., and Uemoto, S.
  • Journal Title: Transplantation. Volume: 87 Pages: 606-614
• [Journal Article] Value of FOXP3 Expression in Peripheral Blood as Rejection Marker After Miniature Swine Lung Transplantation. (2008)
  • Author(s): Satoda, N., Shoji, T., Wu, Y., Fujinaga, T., Chen, F., Aoyama, A., Zhang, J. T., Takahashi, A., Okamoto, T., Matsumoto, I., Sakai, H., Li, Y., Zhao,X., Manabe, T., Kobayashi, E., Sakaguchi, S., Wada, H., Ohe, H., Uemoto, S., Tottori, J., Bando, T., Date
  • Journal Title: J. Heart Lung Transplant Volume: 27 Pages: 1293-1301
• [Journal Article] CTLA-4 control over Foxp3+regulatory T cell function (2008)
  • Author(s): Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., and Sakaguchi, S.
  • Journal Title: Science. Volume: 322 Pages: 271-275
• [Journal Article] The presence of FOXP3 expressing T cells within grafts of tolerance human liver transplant recipients. (2008)
  • Author(s): Li, Y., Zhao, X., Cheng, D., Haga, H., Tsuruyama, T., Wood, K., Sakaguchi, S., Tanaka, K., Uemoto, S., and Koshiba, T.
  • Journal Title: Transplantation Volume: 86 Pages: 1837-1843
• [Journal Article] Foxp3+natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. (2008)
  • Author(s): Onishi, Y., Fehervari, Z., Yamaguchi, T., and Sakaguchi, S
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 29 Pages: 10113-10118
• [Journal Article] Regulatory T cells and immune tolerance (2008)
  • Author(s): Sakaguchi, S., Yamaguchi, T., Nomura, T., and Ono, M.
  • Journal Title: Cell Volume: 133 Pages: 775-787
• [Journal Article] Regulatory T cellsin the past and for the future. (2008)
  • Author(s): Sakaguchi, S.
  • Journal Title: ur. J. Immunol. Volume: 38 Pages: 901-937
• [Journal Article] Construction of self-recognizing regulatory T cells from conventional T cells by controllingCTLA-4 and IL-2 expression.
  • Author(s): Yamaguchi T, Kishi A, Osaki M, Morikawa H, Prieto-Martin P, Wing K, Saito T, and Sakaguchi S.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: (In press)
• [Presentation] Regulatory T cells for self-tolerance. (2010)
  • Author(s): Shimon Sakaguchi
  • Organizer: 14thInternational Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 20100822-27
• [Presentation] T cell signaling, regulatory T cells, and self-tolerance. (2010)
  • Author(s): Shimon Sakaguchi
  • Organizer: 97thAnnual Meeting of the American Association of Immunologist
  • Place of Presentation: Baltimore, USA
  • Year and Date: 20100507-11
• [Presentation] Regulatory T cells for the control of immunological diseases. (2008)
  • Author(s): Shimon Sakaguchi
  • Organizer: 2008 Keio Medical Science Prize Commemorative Symposium
  • Place of Presentation: 東京
  • Year and Date: 2008-11-22
• [Patent(Industrial Property Rights)] Induction of Regulatory T Cell-resistant Helper CD4+ T Cells (2008)
  • Inventor(s): Nishikawa, H; Tsuji, T; Ritter, G; Old, LJ; Galan, JE
  • Industrial Property Rights Holder: LICR 12/262831
  • Industrial Property Number: 12/262831
  • Filing Date: 2008-10-31
  • Overseas