免疫寛容の誘導・維持と破綻における樹状細胞の機能と作用メカニズムの解析

• Project/Area Number: 13140202
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 稲葉 カヨ 京都大学, 生命科学研究科, 教授 (00115792)
• Co-Investigator(Kenkyū-buntansha): 伊豫田 智典 京都大学, 生命科学研究科, 助手 (60359784) ; 高原 和彦 京都大学, 大学院・生命科学研究科, 講師 (90301233)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥136,500,000 (Direct Cost: ¥136,500,000); Fiscal Year 2005: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2004: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2003: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2002: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2001: ¥28,500,000 (Direct Cost: ¥28,500,000)
• Keywords: 樹状細胞 / 免疫応答制御 / 制御性T細胞 / 抗原提示 / T細胞活性化 / 抗原特異性 / クロストレランス / クロストプライミング / Th1 / Th2 / 補助刺激分子 / 免疫寛容 / CD25^+CD4^+制御性T細胞 / CD80 / 86 / サブセット / 抗原捕捉 / クロスプレゼンテイーション / T細胞増殖 / T細胞除去 / IFN-γ / 樹状細胞活性化

Research Abstract

胸腺由来のCD25+CD4+制御性T細胞(Treg)は自己免疫疾患の発症を抑制していることが知られるが、活性化した樹状細胞(DC)はTregの増殖を誘導し、免疫応答を制御することもこれまでの研究で明らかである。また、DCによって増殖したTregはその抗原特異性を維持し免疫応答を抑制する。そこで、異系白血球混合培養応答(MLR)によって増殖するTregの特異性とその効率をin vitroならびにin vivoで検討した。その結果、異系DCはIL-2非添加に比べ添加時に非常に効率よくTregの増殖を誘導すること、IL-2およびCD80/86非依存的にFoxp3の発現を維持することが示された。また、増殖したTregは生体から調製された直後の細胞に比べ、遥かに強力にMLRを抑制すること、また、増殖誘導に用いられたDCの系統に対するMLRの抑制活性は別の系統に対するものに比べ3-10倍であった。そこで、この細胞を同系のCD25-CD4+ T細胞と共に亜致死線量を照射した異系マウスに輸注したところ、GvHの発症が有意に抑制されることも示された。
このようなTregの増殖誘導に関しては、骨髄前駆細胞よりin vitroで誘導された活性化DCがとりわけ強力な作用をもつことから、生体から調製した脾DCによる抗原提示における作用を検討した。その結果、脾DCはナイーブな抗原特異的T細胞だけでなく、増殖誘導した抗原特異的Tregの増殖も誘導した。しかし、培養過程におけるDCのMHCクラスIIならびにCD80の発現上昇はTregと培養した場合には認められなかった。さらに、抗原特異性の異なるTregとナイーブT細胞を両方の抗原を提示する同時に提示するDCと共に培養すると、ナイーブT細胞の活性化が有意に抑制されることが明らかになった。

Research Products

• [Journal Article] Phagocytosis of co-developing megakaryocytic progenitors by dendritic cells in culture with thrombopoietin and tumor necrosis factor-α and its possible role in hemophagocytic syndrome (2006)
  • Author(s): Kunie Saito
  • Journal Title: Blood 107(4) Pages: 1366-1374
• [Journal Article] Effective expansion of alloantigen-specific foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction (2006)
  • Author(s): Sayuri Yamazaki
  • Journal Title: Pro.Natl.Acad.Sci.USA.
• [Journal Article] Expression and its regulation of a polymorphic inhibitory NK receptor Ly49Q on dendritic cells subsets (2005)
  • Author(s): Noriko Toyama-Sorimachi
  • Journal Title: J.Immunol. 174(8) Pages: 4621-4629
• [Journal Article] Engagement of human monocyte-derived dendritic cells into interleukin (IL)-12 producer by IL-1β + IFN-γ (2005)
  • Author(s): Takeshi Nakahara
  • Journal Title: Clin.Exp.Immunol. 139(3) Pages: 476-782
• [Journal Article] Development of murine plasmacytoid dendritic cells defined by increased expression of an inhibitory NK receptor, Ly49Q (2005)
  • Author(s): Yoshiki Omatsu
  • Journal Title: J.Immunol. 174(11) Pages: 6657-6662
• [Journal Article] Probing Langerhans cell function by their inducible ablation in mice (2005)
  • Author(s): Clare L.Bennett
  • Journal Title: J.Cell Biol. 169(4) Pages: 562-576
• [Journal Article] Association of SIGNR1 with TLR4/MD-2 enhances signal transduction by ecognition of LPS in Gram-negative bacteria (2005)
  • Author(s): Koji Nagaoka
  • Journal Title: Int.Immunol. 17(7) Pages: 827-836
• [Journal Article] Antigen recognition and presentation by DC (2005)
  • Author(s): Kayo Inaba
  • Journal Title: Int.J.Hematol. 18(3) Pages: 181-187
• [Journal Article] The innate functions of dendritic cells in peripheral lymphoid tissues (2005)
  • Author(s): Ralph M.Steinman
  • Journal Title: Adv.Exp.Med.Biol. 560 Pages: 83-97
• [Journal Article] Expression and its regulation of a polymorphic inhibitory NK receptor Ly49Q on dendritic cells subsets. (2005)
  • Author(s): Toyama-Sorimachi, N.
  • Journal Title: J.Immunol. (in press)
• [Journal Article] Crucial roles of Rap1 effector molecule RAPL in lymphocytes and dendritic cells trafficking. (2004)
  • Author(s): Katagiri, K.
  • Journal Title: Nat.Immunol. 5(10) Pages: 1045-1051
• [Journal Article] Pivotal role of CSCR3 in melanoma cell metastasis to lymph nodes (2004)
  • Author(s): Kawada, K.
  • Journal Title: Cancer Res. 64(11) Pages: 4010-4117
• [Journal Article] Codevelopment of dendritic cells along with erythroid differentiation from human CD34+ cells by tumor necrosis factor-α. (2004)
  • Author(s): Fukaya, H.
  • Journal Title: Exp.Heamatol. 32(5) Pages: 450-460
• [Journal Article] Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins (2004)
  • Author(s): Takahara, K.
  • Journal Title: Int.Immunol. 16(6) Pages: 819-829
  • NAID: 10013085962
• [Journal Article] Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice (2004)
  • Author(s): Oshirna, H.
  • Journal Title: EMBO J. 23(7) Pages: 1669-1678
• [Journal Article] Plasmacytoid dendritic cells regulate helper T cell responses through OX40 ligand and type I interferons. (2004)
  • Author(s): Ito, T.
  • Journal Title: J.Immunol. 172(7) Pages: 4253-4259
• [Journal Article] Molecular Cloning of Human Dectin-2 (2004)
  • Author(s): Kanazawa, N.
  • Journal Title: J Invest Dermatol. 122(6) Pages: 1522-1524
• [Publications] Ito, T.: "Plasmacytoid dendritic cells regulate helper T cell responses through OX40 ligand and type I interferons."J.Immmunol.. 印刷中. (2004)
• [Publications] Ichikawa, E.: "Defective development of splenic and epidermal CD4 dendritic cells in mice deficient for interferon regulatory factor-2."Proc.Natl.Acad.Sci.USA. 101(11). 3909-3914 (2004)
• [Publications] Kanazawa, N.: "Molecular Cloning of Human Dectin-2."J.Invest.Dermatol.. 印刷中. (2004)
• [Publications] Toyama-Sorimachi, N.: "Ly49Q, a novel member of Ly49 family that is selectively expressed on myeloid lineage cells and involved in regulation of cytoskeletal architecture."Proc.Natl.Acad.Sci.USA. 101(4). 1016-1021 (2004)
• [Publications] Kanazawa, N.: "DCAR, a novel C-type lectin immunoreceptor, acts as an activating receptor through its association with Fc receptor γ chain."J.Biol.Chem.. 78(35). 32645-32652 (2003)
• [Publications] Yamazaki, S.: "Expansion of CD25^+ CD4^+ regulatory T cells by antigen-presenting dendritic cells."J.Exp.Med.. 198(2). 235-247 (2003)
• [Publications] Kabashima, K.: "Prostaglandin E_2-EP4 signaling is critically involved in migration and maturation of Langerhans cells in the initiation phase of contact hypersensitivity."Nature Medicine. 9(6). 744-749 (2003)
• [Publications] Kang, Y.-S.: "SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran."Int.Immunol.. 15(2). 177-186 (2003)
• [Publications] Kabashima, K.: "Prostaglandin E2-EP4 signaling is critically involved in migration and maturation of Langerhans cells in the initiation phase of contact hypersensitivity"Nature Medicine. (in press). (2003)
• [Publications] Kang, Y.-S.: "SIGN-R1, a novel C-type lectin expressed by marginal zone macrophagesin spleen, mediates uptake of the polysaccharide dextran"Int.Immunol.. 15(2). 177-186 (2003)
• [Publications] Kusunoki, T.: "TH2 dominance and defective development of a CD8^+ dendritic cell subset in Id2-deficient mice"J Allergy Clin Immunol.. 111(1). 136-142 (2003)
• [Publications] Steinman, R.M.: "Dendritic cell function in vivo during the steady state : A role in peripheral tolerance"Ann. NY Acad.Sci. 987. 1-12 (2003)
• [Publications] Liu, K.: "Immune tolerance after delivery of dying cells to dendritic cells in situ"J.Exp.Med.. 196(8). 1091-1097 (2002)
• [Publications] Ichioka, N.: "Prevention of senile osteoporosis in SAMP6 mice by intrabone marrow injection of allogeneic bone marrow cells"Stem Cells. 20(6). 542-551 (2002)
• [Publications] Iyoda, T: "The CD8^+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo"J.Exp.Med.. 195(10). 1289-1302 (2002)
• [Publications] Takahara, K.: "Identification and Expression of Mouse Langerin (CD207) in Dendritic Cells"Int.Immunol.. 14(5). 433-444 (2002)
• [Publications] Kanazawa, N.: "DCIR acts as an inhibitory receptor depending on its immunoreceptor tyrosine-based inhibitory motif"J.Invest.Dermatol.. 118(2). 261-266 (2002)
• [Publications] Takahara, K.: "Identification and Expression of Mouse Langerin (CD207) in Dendritic Cells"Int. Immunol.. (in press). (2002)
• [Publications] Kanazawa, N.: "DCIR acts as an inhibitory receptor depending on its immunoreceptor tyrosine-based inhibitory motif"J. Invest. Dermatol.. (in press). (2002)
• [Publications] Park, C.-G: "Five mouse homologues of the human dendritic cell C-type Lectin, DC-SIGN"Int. Immunol.. 13(10). 1283-1290 (2001)
• [Publications] Hawigger, D.: "Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo"J. Exp. Med.. 194(6). 769-780 (2001)
• [Publications] Hemmi, H.: "Skin antigens in steady state are trafficked to regional lymph nodes by transforming growth factor-β1-dependent cells"Int. Immunol.. 13(5). 695-704 (2001)
• [Publications] Ito.T.: "Regulation of myeloid and lymphoid dendritic cell functions by interferons and relevant cytokines"J. Immunol.. 166(5). 2961-2969 (2001)