Basic study of molecular target therapy for autoimmune diseases and immune deficiency diseases based on CD26

基于CD26的自身免疫性疾病及免疫缺陷病分子靶向治疗基础研究

• 批准号: 15209033
• 负责人: MORIMOTO Chikao
• 金额: $ 26.79万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15209033/
• 关键词: CD26; CD45RA; cord T cell; CD86; interference RNA; Caveolin-1; Tetanus Toxid; CD28; 可溶性CD26; リガンド; dipepetidyl peptidase IV; アデノシンデアミナーゼ; リピッドラフト; T細胞シグナル; GVHD

CD26 is a T-cell activation antigen that contains dipeptidyl peptidase IV activity and binds adenosine deaminase. We investigate the role of CD26 in cord blood T-cell activation and signal transduction. We demonstrated that different expression levels of CD26 were observed between cord blood T cells(CBTCs) and peripheral blood T cells(PBTCs) and that CD26(+)CD45RA(+) CBTCs were different compared with CD26(+)CD45RA(+) PBTCs. Moreover, the comitogenic effect of CD26 was not as pronounced in CBTCs as in PBTCs. We also showed that CD26 cross-linking induced less phosphorylation of T-cell receptor-signaling molecules, lymphoid T-cell protein tyrosine kinase(Lck), zeta-associated protein 70(ZAP-70), T-cell receptor zeta(TCRzeta), and linker for activator of T cells(LAT) in CBTCs than in PBTCs. Furthermore, CD26 molecules associated with CD45RA molecules outside lipid rafts in CBTCs. Our results suggest that strong physical linkage of CD26 with CD45RA outside lipid rafts may be responsible f … More or the attenuation of T-cell activation signaling through CD26, which may be responsible for immature immune response and the low incidence of severe graft-versus-host disease in cord blood transplantation.We previously reported that recombinant soluble CD26 enhanced T cell proliferation induced by the recall antigen tetanus toxoid(TT). However, the mechanism involved in this enhancement is not yet elucidated. We now demonstrate that CD26 binds Caveolin-1 on antigen-presenting cells, and that residues 201-211 of CD26 along with the serine catalytic site at residue 630 contribute to binding to caveolin-1 scaffolding domain. In addition, after CD26-caveolin-1 interaction on TT-loaded monocytes, caveolin-1 is phosphorylated, which links to activate NF-kappaB, followed by up-regulation of CD86. Finally, reduced caveolin-1 expression on monocytes inhibits CD26-mediated CD86 up-regulation and abrogates CD26 effect on TT-induced T cell proliferation. Taken together, these results strongly suggest that CD26-caveolin-1 interaction plays a role in the up-regulation of CD86 on monocytes and subsequent engagement with CD28 on T cells, leading to antigen-specific T cell activation. Less

CD26 是一种 T 细胞激活抗原，含有二肽基肽酶 IV 活性并结合腺苷脱氨酶。我们研究 CD26 在脐带血 T 细胞激活和信号转导中的作用。我们证明，脐带血T细胞（CBTC）和外周血T细胞（PBTC）之间观察到CD26的表达水平不同，并且CD26（+）CD45RA（+）CBTC与CD26（+）CD45RA（+）PBTC相比是不同的。此外，CD26 的致精作用在 CBTC 中不如 PBTC 中那么明显。我们还发现，与 PBTC 相比，CD26 交联在 CBTC 中诱导的 T 细胞受体信号分子、淋巴 T 细胞蛋白酪氨酸激酶 (Lck)、zeta 相关蛋白 70 (ZAP-70)、T 细胞受体 zeta (TCRzeta) 和 T 细胞激活剂接头 (LAT) 的磷酸化较少。此外，CD26 分子与 CBTC 中脂筏外的 CD45RA 分子相关。我们的结果表明，脂筏外CD26与CD45RA的强烈物理连接可能是通过CD26减弱T细胞激活信号的原因，这可能是导致脐带血移植中免疫反应不成熟和严重移植物抗宿主病发生率低的原因。我们之前报道过，重组可溶性CD26增强了由破伤风回忆抗原诱导的T细胞增殖 类毒素（TT）。然而，这种增强所涉及的机制尚未阐明。我们现在证明CD26结合抗原呈递细胞上的Caveolin-1，并且CD26的残基201-211以及残基630处的丝氨酸催化位点有助于结合caveolin-1支架结构域。此外，在加载 TT 的单核细胞上 CD26-caveolin-1 相互作用后，caveolin-1 被磷酸化，从而激活 NF-kappaB，随后上调 CD86。最后，单核细胞上的 Caveolin-1 表达减少会抑制 CD26 介导的 CD86 上调，并消除 CD26 对 TT 诱导的 T 细胞增殖的影响。总而言之，这些结果强烈表明 CD26-caveolin-1 相互作用在单核细胞上 CD86 的上调以及随后与 T 细胞上 CD28 的结合中发挥作用，从而导致抗原特异性 T 细胞激活。较少的

项目成果

Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation.

CD26 与脂筏外 CD45RA 的结合会减弱脐带血 T 细胞的活化。

• DOI: 10.1182/blood-2003-08-2691
• 发表时间: 2004
• 期刊: Blood
• 影响因子: 20.3
• 作者: Kobayashi,Seiji;Ohnuma,Kei;Uchiyama,Masahiko;Iino,Kouichi;Iwata,Satoshi;Dang,NamH;Morimoto,Chikao
• 通讯作者: Morimoto,Chikao

HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L).

HTLV-I Tax 诱导并与 Crk 相关底物淋巴细胞类型 (Cas-L) 相关。

• 发表时间: 2005
• 期刊: Oncogene 24
• 作者: Iwata S;Morimoto C;et al.
• 通讯作者: et al.

Ishii T, et al.: "SSA/Ro52,an autoantigen involved in CD28-mediated IL-2 production."J.Immunol. 170. 95-107 (2003)

Ishii T 等人：“SSA/Ro52，一种参与 CD28 介导的 IL-2 产生的自身抗原。”J.Immunol。

Nedd9 Protein, a Cas-L Homologue, Is Upregulated After Transient Global Ischemia in Rats: Possible Involvement of Nedd9 in the Differentiation of Neurons After Ischemia

• DOI: 10.1161/01.str.0000185672.10390.30
• 发表时间: 2005-11
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Takahiro Sasaki;S. Iwata;H. Okano;Y. Urasaki;Junichi Hamada;Hirotoshi Tanaka;N. Dang;H. Okano;C. Morimoto

Kobayashi S, et al.: "Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation."Blood. 103. 1002-1010 (2004)

Kobayashi S 等人：“脂筏外部 CD26 与 CD45RA 的结合会减弱脐带血 T 细胞的活化。”血液。