OX40 signaling renders adult T-cell leukemia cells resistant to Fas-induced apoptosis.

We reported previously that OX40, a member of the tumor necrosis factor receptor family, is expressed constitutively on fresh leukemia/lymphoma cells isolated from patients with adult T-cell leukemia (ATL). In this study, we tested whether OX40 signaling affects the Fas-mediated apoptosis of fresh ATL cells isolated from 7 patients (3 acute type, 3 chronic type, and 1 smoldering type). In all these patients, the coculture of ATL cells with MMCE/OX40 ligand gp34, a stable human gp34 transfectant of a mouse epithelial cell line, resulted in a decrease in the percentage of apoptotic cells after treatment with anti-Fas monoclonal antibody, compared to coculture with MMCE/mock controls. Similar findings were obtained in OX40(+)- human T-cell leukemia virus type I-transformed T-cell lines. To elucidate the molecular mechanism of this phenomenon, we used Kit225/OX40, a stable OX40 transfectant of an IL-2-dependent T-cell line, and its deletion mutant, Kit225/del-OX40, in which the intracytoplasmic domain of OX40 had been deleted. Coculture with MMCE/gp34 inhibited the apoptosis of Kit225/OX40, but Kit225/del-OX40 apoptosis was hardly affected. These results suggest that ATL cells may escape Fas-mediated destruction of the immune system through OX40 signaling.