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

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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.