Molecular basis and therapeutic target for autoimmune arthritis

• Project/Area Number: 26253030
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• 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): 廣田 圭司 京都大学, 再生医科学研究所, 准教授 (90631250)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥40,430,000 (Direct Cost: ¥31,100,000、Indirect Cost: ¥9,330,000); Fiscal Year 2016: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000); Fiscal Year 2015: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000); Fiscal Year 2014: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
• Keywords: SKG / 自己免疫性関節炎 / 関節リウマチ / ZAP-70 / 自己抗原

Outline of Final Research Achievements

In this study, we have developed a new mouse model system with different ZAP-70 functions to understand the development and autoimmune function of T helper cells and identified a particular range of ZAP-70 function associated with the developmental arrest of T cells in the thymus and generation of arthritogenic T helper cells. We have also established a novel retrogenic mouse system to identify auto-antigens recognized by arthritogenic T cells isolated from inflamed joints of SKG mice and demonstrated that T cells specific for the auto-antigen RPL23A induced psoriasis-like skin disease and arthritis. Anti-RPL23A auto-antibody was specific to patients with rheumatoid arthritis, indicating that this screening system for auto-antigens is useful for identifying novel therapeutic targets and new biomarkers for rheumatoid arthritis.

Research Products

• [Journal Article] Advertisement Hypomethylation of the Treg-specific demethylated region in FOXP3 is a hallmark of the regulatory T-cell subtype in adult T-cell leukemia (2016)
  • Author(s): Shimazu Y, Shimazu Y, Hishizawa M, Hamaguchi M, Nagai Y, Sugino N, Fujii S, Kawahara M, Kadowaki N, Nishikawa H, Sakaguchi S, Takaori-Kondo A.
  • Journal Title: Cancer Immunol Res. Volume: 4 Pages: 136-145
  • Peer Reviewed / Open Access
• [Journal Article] Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. (2015)
  • Author(s): Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, Claër L, Hingorani R, Balderas R, Rohrer J, Warner N, Chapelier A, Valeyre D, Kannagi K, Sakaguchi S, Amoura Z, Gorochov G.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 112 Pages: 7225-7230
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transcriptional and epigenetic control of regulatory T cell development. (2015)
  • Author(s): Kitagawa Y, Wing JB, Sakaguchi S.
  • Journal Title: Prog Mol Biol Transl Sci. Volume: 136 Pages: 1-33
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The microbiota regulates type 2 immunity through RORt+ T cells. (2015)
  • Author(s): Ohnmacht C, Park J, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G.
  • Journal Title: Science. Volume: 349 Pages: 989-993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals (2014)
  • Author(s): Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T, Nishioka M, Wing JB, Adeegbe D, Katayama I, Sakaguchi S.
  • Journal Title: Science Volume: 346 Pages: 1536-1540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of T-cell responses to a ubiquitous cellular protein in autoimmune disease (2014)
  • Author(s): Ito Y, Hashimoto M, Hirota K, Ohkura N, Morikawa H, Nishikawa H, Tanaka A, Furu M, Ito H, Fujii T, Nomura T, Yamazaki S, Morita A, Vignali DA, Kappler JW, Matsuda S, Mimori T, Sakaguchi N, Sakaguchi S.
  • Journal Title: Science Volume: 346 Pages: 363-368
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulatory T-cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4 (2014)
  • Author(s): Wing JB, Ise W, Kurosaki T, Sakaguchi S.
  • Journal Title: Immunity Volume: 41 Pages: 1013-1025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-10- Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation (2014)
  • Author(s): Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, Kallies A, Nutt SL, Sakaguchi S, Takeda K, Kurosaki T, and Baba Y.
  • Journal Title: Immunity Volume: 41 Pages: 1040-1051
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Schmidt-Supprian M. Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool (2014)
  • Author(s): Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, RieB D, Hein MY, Buch T, Polic B, Schonle A, Zeiser R, Schmitt-Graff A, Kretschmer K, Klein L, Korn T, Sakaguchi S
  • Journal Title: Immunity Volume: 41 Pages: 722-736
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin. (2014)
  • Author(s): Yamazaki S, Nishioka A, Kasuya S, Ohkura N, Hemmi H, Kaisho T, Taguchi O, Sakaguchi S, Morita A.
  • Journal Title: J Immunol Volume: 193 Pages: 5488-5497
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epigenetic control of thymic Treg-cell development. (2014)
  • Author(s): Kitagawa Y, Ohkura N, Sakaguchi S.
  • Journal Title: Eur. J. Immunol Volume: 45 Pages: 11-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] FRT - Fondation Rene Touraine: Pour La Dermatologie. (2014)
  • Author(s): Sakaguchi S, Sallusto F, Gebhardt T, Stingl G, Clark RA, Santamaria-Babí LF, Guttman-Yassky E, Schuler G, Koenen HJ.
  • Journal Title: Exp Dermatol Volume: 23 Pages: 772-785
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. (2014)
  • Author(s): Morikawa H, Ohkura N, Vandenbon A, Itoh M, Nago-Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest A, Standley D, Date D, Sakaguchi S, and the FANTOM consortium.
  • Journal Title: PNAS Volume: 111 Pages: 5289-5294
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer. (2014)
  • Author(s): Pastille E, Bardini K, Fleissner D, Adamczyk A, Frede A, Wadwa M, von Smolinski D, Kasper S, Sparwasser T, Gruber AD, Schuler M, Sakaguchi S, Roers A, Miiller W, Hansen W, Buer J, Westendorf AM.
  • Journal Title: Cancer Res. Volume: 74 Pages: 4258-4269
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive exploration of autoantibody in Behçet's disease: A novel autoantibody to claudin-1, an essential protein for tight junctions, is identified. (2014)
  • Author(s): Morishima A, Hirano T, Nishikawa H, Nakai K, Sakaguchi S, Kumanogoh A.
  • Journal Title: Joint Bone Spine. Volume: 81 Pages: 546-548
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD28 signals the differential control of regulatory T cells and effector T cells. (2014)
  • Author(s): Mikami N, Sakaguchi S.
  • Journal Title: Eur J Immunol Volume: 44 Pages: 955-957
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TREG-cell therapies for autoimmune rheumatic diseases. (2014)
  • Author(s): Miyara M, Ito Y, Sakaguchi S.
  • Journal Title: Nat Rev Rheumatol. Volume: 10 Pages: 543-551
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic and epigenetic basis of Treg cell development and function: From a FoxP3-centered view to an epigenome-defined view of natural Treg cells (2014)
  • Author(s): Morikawa H, Sakaguchi S.
  • Journal Title: Immunol. Rev Volume: 259 Pages: 192-205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A promoter level mammalian expression atlas. (2014)
  • Author(s): Forrest A, ..., Morikawa H., ..., Hamaguchi M., ..., Ohkura N., ...,Sakaguchi S., ...,Hayashizaki Y, et al.,
  • Journal Title: Nature Volume: 507 Pages: 462-470
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Foxp3+ Treg cells in humoral immunity. (2014)
  • Author(s): Wing JB, Sakaguchi S.
  • Journal Title: Int Immunol. Volume: 26 Pages: 61-69
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD8+ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma (2014)
  • Author(s): Fujii H, Arakawa A, Utsumi D, Sumiyoshi S, Yamamoto Y, Kitoh A, Ono M, Matsumura Y, Kato M, Konishi K, Shiga T, Sano S, Sakaguchi S, Miyagawa-Hayashino A, Takahashi K, Uezato H, Miyachi Y, Tanioka M.
  • Journal Title: Int J Cancer Volume: 134 Pages: 2393-2402
  • NAID: 120005458273
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulatory T cells in cancer immunotherapy. (2014)
  • Author(s): Nishikawa H, Sakaguchi S.
  • Journal Title: Curr Opin Immunol. Volume: 27 Pages: 1-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of glucocorticoid-induced TNFR-related protein (GITR) ligand in effector function and Treg-mediated suppression (2015)
  • Author(s): Yasuda Keiko, Nishioka Tomohisa, Hirota Keiji, Takeda Kiyoshi, Akira Shizuo, Sakaguchi Shimon
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Presentation] Regulation of immune responses by sCTLA-4 produced by Treg cells (2015)
  • Author(s): Osaki Motonao, Sakaguchi Shimon
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Presentation] Establishment of regulatory T cell-specific super-enhancers (2015)
  • Author(s): Kitagawa Yohko, Ohkura Naganari, Sakaguchi Shimon
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Presentation] Specific characteristics of tumor infiltrating regulatory T cells (2015)
  • Author(s): Kidani Yujiro, Sakaguchi Shimon, Ohkura Naganari
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Presentation] Rheumatoid arthritis patients-derived gut microbiota induce Th17-mediated arthritis in SKG Mice (2015)
  • Author(s): Maeda Yuichi, Umemoto Eiji, Matsushita Masato, Saeki Yukihiko, Ito Yoshinaga, Hirota Keiji, Sakaguchi Noriko, Kumanogo Atushi, Sakaguchi Shimon, Takeda Kiyoshi
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Presentation] Control of Immune Responses by Regulatory T cells (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: KEYSTONE SYMPOSIA T Cells: Regulation and Effector Function
  • Place of Presentation: Utah（USA）
  • Year and Date: 2015-03-29 – 2015-04-03
  • Invited
• [Presentation] APC and T Regs (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: KEYSTONE SYMPOSIA Dendritic Cells and Macrophages Reunited
  • Place of Presentation: Montreal（Canada）
  • Year and Date: 2015-03-08 – 2015-03-13
  • Invited
• [Presentation] Control of immune responses by regulatory T cells. (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 4th NIF Winter School on Advanced Immunology
  • Place of Presentation: Singapore
  • Year and Date: 2015-01-18 – 2015-01-23
  • Invited
• [Presentation] Regulatory T Cells and Immune Tolerance. (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: Sushruta Lecture Transplantation Update-2015
  • Place of Presentation: Ahmedabad（India）
  • Year and Date: 2015-01-09 – 2015-01-11
  • Invited
• [Presentation] Control of autoimmunity and tumor immunity by regulatory T cells (2014)
  • Author(s): 坂口志文
  • Organizer: 日本研究皮膚科学会第39回年次学術大会・総会
  • Place of Presentation: ホテル阪急エキスポパーク（大阪）
  • Year and Date: 2014-12-14
  • Invited
• [Presentation] The soluble form of CTLA-4 in regulatory T cells-mediated suppression (2014)
  • Author(s): Osaki Motonao, Sakaguchi Shimon
  • Organizer: 第43回日本免疫学会総会・学術総会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The genome organizer Satb1 differentially controls thymic and peripheral development of regulatory T cells. (2014)
  • Author(s): 4.Kitagawa Yohko, Ohkura Naganari, Hirota Keiji, Adeegbe Olakunle, Yasada Keiko, Kondo Motonari, Taniuchi Ichiro, Kohwi-ShigematuTerumi, Sakaguchi Shimon
  • Organizer: 第43回日本免疫学会総会・学術総会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Regulatory T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: development, maintenance and function in normal and disease states 22nd FRT –Fondation Rene Touraine Annual Scientific Meeting
  • Place of Presentation: Paris（France）
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] Keynote Address Immune Regulation for Cancer Immunotherapy The 45th International Symposium of The Princess Takamatsu Cancer Research Fund (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Recent Advances in Cancer Immunotherapy
  • Place of Presentation: パレスホテル東京（東京）
  • Year and Date: 2014-11-18 – 2014-11-20
  • Invited
• [Presentation] 制御性T細胞と自己免疫・癌 (2014)
  • Author(s): 坂口志文
  • Organizer: 第57回日本甲状腺学会学術集会
  • Place of Presentation: ナレッジキャピタル コングレコンベンションセンター（大阪）
  • Year and Date: 2014-11-13 – 2014-11-15
  • Invited
• [Presentation] Control of immune responses by regulatory T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: BK seminar Integrative Biosciences and Biotechnology
  • Place of Presentation: Pohan（Korea）
  • Year and Date: 2014-11-10
  • Invited
• [Presentation] Genetic and epigenetic basis of Treg cell development and function. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Academy of Immunology and Microbiology Workshop on Immunology 2014
  • Place of Presentation: Pohan（Korea）
  • Year and Date: 2014-11-09 – 2014-11-10
  • Invited
• [Presentation] Regulatory T Cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Development, Maintenance and Function in Normal and Disease States The 2014 Fall Conference of Korean Association of Immunologists
  • Place of Presentation: Seoul（Korea）
  • Year and Date: 2014-11-06 – 2014-11-07
  • Invited
• [Presentation] Treg-mediated control of the cell fate of autoimmune T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: The Fourth International Conference on Regulatory T Cells and T Helper Cell Subsets and Clinical Application in Human Diseases
  • Place of Presentation: Shanghai（China）
  • Year and Date: 2014-11-01 – 2014-11-04
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Control of Treg cells for immune tolerance (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Novo nordisk innovation summit Tokyo
  • Place of Presentation: 東京大学医科学研究所（東京）
  • Year and Date: 2014-10-01 – 2014-10-02
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第51回補体シンポジウム
  • Place of Presentation: 神戸常盤大学（神戸）
  • Year and Date: 2014-08-22 – 2014-08-23
  • Invited
• [Presentation] Control of Tumor Immunity by Regulatory T Cells. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: IAAO(International Academy for Advanced Oncology) Convergence for Breakthroughs in Oncology Therapy
  • Place of Presentation: 六本木ヒルズ（東京）
  • Year and Date: 2014-08-01 – 2014-08-02
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第33回分子病理学研究会
  • Place of Presentation: 宮城蔵王ロイヤルホテル（蔵王）
  • Year and Date: 2014-07-25 – 2014-07-26
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第51回日本消化器免疫学会総会
  • Place of Presentation: 京都大学医学部 芝蘭会館（京都）
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] Control of autoimmunity and tumor immunity by regulatory T cells. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: RJKEN IMS-JSI International Symposium on Immunology 2014 Decoding Immune Complexity Bench to Bedside
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第38回日本リンパ学会総会東京
  • Place of Presentation: 北里大学白金キャンパス薬学部コンベンションホール（東京）
  • Year and Date: 2014-06-21
  • Invited
• [Presentation] Regulatory T cells in autoimmunity and tumor immunity (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 1st joint symposium of Karolinska Institute and Osaka University 2014 Immunology and Infection biology
  • Place of Presentation: Stockholm（Sweden）
  • Year and Date: 2014-06-10
  • Invited
• [Presentation] Epigenetic changes and Treg cell development. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: European Academy of Allergy and Clinical Immunology Congress 2014
  • Place of Presentation: Copenhagen（Denmark）
  • Year and Date: 2014-06-07 – 2014-06-11
  • Invited
• [Presentation] 胸腺と末梢の制御性T細胞発生におけるSATB1の役割 (2014)
  • Author(s): 北川瑤子、大倉永也、廣田圭司、安田佳子、谷内一郎、近藤元就、重松照美、坂口志文
  • Organizer: 第24回Kyoto T Cell Conference
  • Place of Presentation: 京都平安ホテル(京都）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] Genetic and epigenetic basis of Treg cell development and function. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: 2014 Beijing-Shanghai Immunology Joint Symposium
  • Place of Presentation: Hangzhou（China）
  • Year and Date: 2014-04-12
  • Invited