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

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。我们以前曾报道，OX 40或TNF-R的各自的HIV-1潜伏感染的ACH-2/OX 40细胞的配体的单独刺激，导致通过NF-κ B途径的HIV-1生产的激活。在本研究中，我们研究了OX 40 L和TNF双重刺激对HIV-1活化的影响。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。

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.