title: Enhancement of OX40-induced apoptosis by TNF coactivation in OX40-expressing T cell lines in vitro leading to decreased targets for HIV type 1 production.
abstract: OX40, a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been shown to play an important role in the survival of antigen-specific CD4(+) T cells. We have previously reported that stimulation of the OX40-expressing and HIV-1 chronically infected T cell line, ACH-2/OX40, with either OX40 ligand (OX40L)-expressing cells or with TNF resulted in the activation of HIV-1 followed by apoptotic cell death. In the present study we found that costimulation via OX40 and TNF-R in OX40-expressing HIV-1-infected T cell lines leads to a marked reduction of HIV-1 production associated with rapid cell death. Since HIV-1-negative OX40(+) T cell lines underwent rapid apoptotic cell death after OX40L and TNF stimulation, it was reasoned that the ACH-2/OX40 cell death was unlikely to be due to HIV-1 infection. Furthermore, we found that the OX40-mediated apoptosis of the CD4(+) T cell line, Molt-4/CCR5-OX40 (M/R5-OX40), required (1) signals mediated via the cytoplasmic tail of OX40, (2) activation of the caspase cascade, including caspase-8 and caspase-3, and (3) induction of endogenous TNF-alpha, but not of TNF-beta, FasL, or TNF-related apoptosis-inducing ligand (TRAIL), suggesting that this apoptosis occurred indirectly via the TNF/TNF-R system. Finally, a fraction of primary activated CD4(+) T cells, expressing high levels of OX40, underwent apoptosis, as revealed by annexin V staining, after cocultivation with OX40L(+) cells. These results suggest a new biological role of the OX40L/OX40 system in controlling the fate of activated CD4(+) T cells and of controlling HIV-1 infection in inflammatory environments.
authors.affiliation: Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D051379:Mice; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry* / Q000276:immunology / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D017304:Annexin A5; D016655:HIV Core Protein p24; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; D014409:Tumor Necrosis Factor-alpha; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D053148:Caspase 3; D053181:Caspase 8