Apoptosis of helper T cells via the costimulatory molecules OX40 stimulated by gp34

gp34 刺激的共刺激分子 OX40 导致辅助 T 细胞凋亡

• 批准号: 14599010
• 负责人: TANAKA Yuetsu
• 金额: $ 2.24万
• 依托单位: University of the Ryukyus
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14599010/
• 关键词: OX40; apoptosis; TNF-R; HIV-1; CD4; OX40

OX40 belongs to TNF receptor(TNF-R) super family and plays an important role in survival of antigen-pecific CD4^+ T cells. We have previously reported that the individual stimulation of OX40 or TNF-R by respective ligands of HIV-1-latently infected ACH-2/OX40 cells results in the activation of HIV-1 production via the NF-kB pathway. In the present study, we examined the effect of dual stimulation by OX40L and TNF on HIV-1 activation. In contrast to individual stimulation, HIV-1 production was severely interrupted by the dual stimulation, which was reversed by anti-OX40L antibody. Similar effects were also observed in other OX40-expressing, HIV-1 productively-chronically-and acutely-infected cells, Molt4/IIIB, U1 and Molt4, respectively. Microscopic observation of cell morphology and Annexin-V staining showed that the double-stimulated cells rapidly became apoptotic. The dual stimulation also induced cell death in T cell lines that were not infected with HIV-1(Molt-4/OX40,CEM/OX40 and Jurkat/OX40). In contrast, two promonocytic cell lines(U937/OX40 and THP-1/OX40) were relatively resistant, and a B cell line(BJAB/OX40) was completely resistant to the dual stimulation. A broad caspase inhibitor, Z-VAD-FMK, significantly reduced the death of Molt-4/OX40 cells. These results suggest a new biological role of OX40 in controlling not only HIV-1 production but also the fate of CD4^+ T cells in infection and inflammatory environments.

OX 40属于肿瘤坏死因子受体（TNF-R）超家族，在抗原特异性CD 4 ^+ T细胞的存活中起重要作用。我们之前曾报道过，潜伏感染HIV-1的ACH-2/OX 40细胞的相应配体对OX 40或TNF-R的单独刺激会导致通过NF-kB途径激活HIV-1的产生。在本研究中，我们检查了OX 40 L和TNF的双重刺激对HIV-1激活的影响。与单独刺激相反，HIV-1的产生被双重刺激严重中断，这被抗OX 40 L抗体逆转。在其他表达OX 40的HIV-1慢性和急性感染细胞Molt 4/IIIB、U1和Molt 4中也观察到类似的效果。细胞形态学观察和Annexin-V染色显示，双重刺激的细胞迅速凋亡。双重刺激还诱导未感染HIV-1的T细胞系（Molt-4/OX 40、CEM/OX 40和Jurkat/OX 40）中的细胞死亡。两个前单核细胞系（U937/OX 40和THP-1/OX 40）对双重刺激相对抵抗，一个B细胞系（BJAB/OX 40）对双重刺激完全抵抗。广泛的caspase抑制剂Z-VAD-FMK显著减少Molt-4/OX 40细胞的死亡。这些结果表明，OX 40不仅控制HIV-1的产生，而且还控制感染和炎症环境中CD 4 ^+ T细胞的命运，这是一种新的生物学作用。

项目成果

Seko Y, Ishiyama S, Tanaka Y et al.: "Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L,CD30L,OX40L and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyppathy."Cardiovasc Pathol.. 11. 166-170 (

Seko Y、Ishiyama S、Tanaka Y 等人：“肿瘤坏死因子配体超家族共刺激分子 CD27L、CD30L、OX40L 和 4-1BBL 在急性心肌炎和扩张型心肌病患者心脏中的表达。”Cardiovasc Pathol.. 11。

Matsumura Y, Hattori T, Tanaka Y, 他5名: "Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin"Arch.Dermatol.Res.. 294. 563-566 (2003)

Matsumura Y、Hattori T、Tanaka Y 和其他 5 人：“CD134 和 CD134 配体在病变和非病变银屑病皮肤中的表达”Arch.Dermatol.Res.. 294. 563-566 (2003)

Matsumura Y, Hattori T, Tanaka Y,. et al.: "Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin."rch.Dermatol.Res.. 294. 563-566 (2003)

松村 Y，服部 T，田中 Y，。

Seko Y, Ishiyama S, Tanaka Y, et al.: "Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L and 4-1BBL in the heart of patients with acute myocarditis dilated cardiomyopathy."Cardiovasc Pathol.. 11. 166-170 (2

Seko Y、Ishiyama S、Tanaka Y 等人：“急性心肌炎扩张型心肌病患者心脏中肿瘤坏死因子配体超家族共刺激分子 CD27L、CD30L、OX40L 和 4-1BBL 的表达。”Cardiovasc Pathol.. 11。

Matsumura Y, Hattori T, Tanaka Y, et al.: "Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin."Arch.Dermatol.Res.. 294. 563-566 (2003)

Matsumura Y、Hattori T、Tanaka Y 等人：“病变和非病变银屑病皮肤中 CD134 和 CD134 配体的表达。”Arch.Dermatol.Res.. 294. 563-566 (2003)