Functional analyses of dendritic subsets in immune regulation

树突亚群在免疫调节中的功能分析

• 批准号: 16390116
• 负责人: INABA Kayo
• 金额: $ 9.6万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390116/
• 关键词: dendritic cells; subset; immune regulation; cytokines; type I interferon; cell differentiation; 分化; 表現型; ランゲルハンス細胞; 移動能; 接触性過敏応答; 真皮樹状細胞

In this project, we examined functional differences of endocytoic conventional dendritic cells (DCs) with type I interferon-producing plasmacyotoid preDCs (P-preDCs) in immune regulations in terms of cytokine production, T cell activation, and expansion of regulatory T cells. The following results were obtained.1)Ly49Q is a member of the Ly49 family that is expressed on Gr-1^+ cells, but not on NK and NKT cells. Conventional DCs were found to be negative for Ly49Q, while bone marrow-derived DCs expressed at low level and upregulated by IFN. On the other hand, Ly49Q was expressed on CD11c^+B220^+Gr-1^+P-preDCs in peripheral lymphoid tissues. However, the expression level on P-preDCs were variable in bone marrow. This was ascribed to the difference in differentiation stage of P-preDCs, since Ly49Q was expressed spontaneously upon culture and Ly49Q^+P-preDCs produced larger amounts of IFN-α/β,IL-6 and IL-12 by CpG-ODN.2)CD25^+CD4^+ regulatory or suppressor Tcells (Tregs) is known to maintain immunological self-tolerance, preventing autoimmunity. Previously we have shown that Tregs proliferate and retain their antigen-dependent suppressive functions when the APCs are antigen-loaded mature dendritic cells (DCs). Using allogeneic polyclonal Tregs, DCs were demonstrated to effectively sustain expression of Foxp3 in Tregs and to be potent for the expansion of alloantigen-specific Tregs in the presence of IL-2. Moreover, those expanded Tregs were efficient to suppressed GvHD induced by CD25- CD4- T cells.3)We generated mice that harbor a targeted insertion of a primate DTR in the Langerin locus. LCs were effectively and selectively ablated in adult Langerin-DTR mice within 24 h after injection of DT. Reconstitution of the epidermal LC compartment in the steady state took at least 4 wk. Functional analysis of LC-depleted mice revealed that dermal DCs were able to mediate a cutaneous CHS response.

在这个项目中，我们研究了功能差异的内吞传统的树突状细胞（DC）与I型干扰素生产浆细胞样preDC（P-preDC）在免疫调节方面的细胞因子的生产，T细胞活化，和调节性T细胞的扩增。1）Ly 49 Q是Ly 49家族的成员，其在Gr-1^+细胞上表达，但不在NK和NKT细胞上表达。发现常规DCs对Ly 49 Q是阴性的，而骨髓来源的DCs在低水平表达并且被IFN上调。另一方面，Ly 49 Q在外周淋巴组织中表达于CD 11 c ^+B220^+Gr-1^+P-preDCs上。然而，P-preDCs在骨髓中的表达水平是可变的。这是由于P-preDCs分化阶段的差异，因为Ly 49 Q在培养时自发表达，而Ly 49 Q ^+P-preDCs通过CpG-ODN产生更大量的IFN-α/β、IL-6和IL-12。2）已知CD 25 ^+ CD 4 ^+调节性或抑制性T细胞（Tcells，Tcells）能够维持免疫自身耐受，防止自身免疫。以前，我们已经表明，当APC是抗原负载的成熟树突状细胞（DC）时，TCFs增殖并保留其抗原依赖性抑制功能。使用同种异体多克隆TCLs，DC被证明有效地维持Foxp 3在TCLs中的表达，并且在IL-2存在下对于同种异体抗原特异性TCLs的扩增是有效的。此外，那些扩增的TTRs有效抑制由⑶ 25-⑶ 4- T细胞诱导的GvHD。3）我们产生了在Langerin基因座中具有灵长类DTR的靶向插入的小鼠。在注射DT后24 h内，在成年Langerin-DTR小鼠中有效地和选择性地消融LC。表皮LC室在稳定状态下的重建需要至少4周。LC-耗竭小鼠的功能分析显示，真皮DC能够介导皮肤CHS反应。

项目成果

Probing Langerhans cell function by their inducible ablation in mice.

通过小鼠中朗格汉斯细胞的诱导消融来探索朗格汉斯细胞的功能。

• 发表时间: 2005
• 期刊: J. Cell. Biol. 169

Development of murine plasmacytoid dendritic cells defined by increased expression of an inhibitory NK receptor, Ly49Q

• DOI: 10.4049/jimmunol.174.11.6657
• 发表时间: 2005-06-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Omatsu, Y;Iyoda, T;Inaba, K
• 通讯作者: Inaba, K

Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins.

• DOI: 10.1093/intimm/dxh084
• 发表时间: 2004-06
• 期刊: International immunology
• 影响因子: 4.4
• 作者: K. Takahara;Yusuke Yashima;Y. Omatsu;H. Yoshida;Y. Kimura;Young‐Sun Kang;R. Steinman;Chae Gyu Park;K. Inaba

Association of SIGNR1 with TLR4/MD-2 enhances signal transduction by ecognition of LPS in Gram-negative bacteria.

SIGNR1 与 TLR4/MD-2 的结合可通过革兰氏阴性细菌对 LPS 的识别来增强信号转导。

• 发表时间: 2005
• 期刊: Int.Immunol. 17(7)
• 作者: Hamada;J.;浜田淳一;Sayuri Yamazaki;Kunie Saito;Kunie Saito;Sayuri Yamazaki;Kunie Saito;Sayuri Yamazaki;Ralph M.Steinman;Kayo Inaba;Koji Nagaoka;Clare L.Bennett;Yoshiki Omatsu;Takeshi Nakahara;Noriko Toyama-Sorimachi;Takeshi Nakahara;Noriko Toyama-Sorimachi;Omatsu Yoshiki;Clare L.Bennett;Kayo Inaba;Koji Nagaoka
• 通讯作者: Koji Nagaoka

Crucial roles of Rap1 effector molecule RAPL in lymphocytes and dendritic cells trafficking

Rap1效应分子RAPL在淋巴细胞和树突状细胞运输中的关键作用

• 发表时间: 2004
• 期刊: Nat. Immunol. 5(10)
• 作者: Toyama-Sorimachi;N.;Y.toyoshima;Toyoshima Y;Koko Katagiri
• 通讯作者: Koko Katagiri