title: The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells.
abstract: OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4+ or CD8+ T cells. Although activated T cells may acquire OX40/4-1BB double-positive phenotype and signaling from each receptor is expected to influence cell functions, the relevance between OX40 and 4-1BB has never been investigated before. While we were investigating the expression of OX40 and 4-1BB on activated human T cells, we found that they colocalize. The study of receptor gene-transfected cells showed that both receptors coendocytose and the complex of OX40 and 4-1BB was detected by specific ligands or antibodies (Abs). The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor-associated factor (TRAF) family proteins in a unique manner. Furthermore, the stimulation of OX40/4-1BB rendered cells sensitive to apoptosis induced by TNF-alpha that accompanied reduced activation of nuclear factor-kappaB (NF-kappaB). Finally, the OX40/4-1BB stimulation repressed the mitogen response in activated CD25+CD4+ T cells and preactivated CD8+ T cells. Thus, the OX40/4-1BB heterodimer appears to represent a unique regulatory receptor in activated T cells.
authors.affiliation: University Health Network, 200 Elizabeth St, MBRC-5R425, Toronto, ON, M5G 2C4 Canada.
authors.forename: Bruce Y
authors.initials: BY
authors.lastname: Ma
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.forename: Karoline A
authors.initials: KA
authors.lastname: Hosiawa
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Cameron
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
mesh_terms: D015703:Antigens, CD / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D019281:Dimerization; D004705:Endocytosis; D006801:Humans; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017475:Receptors, Nerve Growth Factor / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000737:chemistry* / Q000276:immunology; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D016328:NF-kappa B; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha