title: Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP.
abstract: K46J B lymphomas express a T cell costimulatory activity that is not inhibited by CTLA-4Ig, anti-B7-1, anti-B7-2, anti-intercellular adhesion molecule 1 or antibodies to heat stable antigen. In this paper we report that this costimulatory activity is mediated at least in part by 4-1BB ligand, a member of the tumor necrosis factor (TNF) gene family that binds to 4-1BB, a T cell activation antigen with homology to the TNF/nerve growth factor receptor family. A fusion protein between 4-1BB and alkaline phosphatase (4-1BB-AP) blocks T cell activation by K46J lymphomas in both an antigen-specific system and with polyclonally (anti-CD3) activated T cells. 4-1BB-AP also blocks antigen presentation by normal spleen cells. When the antigen-presenting cells express B7 molecules as well as 4-1BB ligand, we find that B7 molecules and 4-1BB-AP both contribute to T cell activation. These data suggest that 4-1BB ligand plays an important role in costimulation of IL-2 production and proliferation by T cells. The B lymphoma M12 expresses low levels of 4-1BB-L but can be induced to express higher levels by treatment of the B cells with cAMP, which also induces B7-1 and B7-2 in these cells. Thus cAMP appears to coordinately induce several costimulatory molecules on B cells.
authors.affiliation: Department of Immunology, University of Toronto, Ontario, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: DeBenedette
authors.forename: N R
authors.initials: NR
authors.lastname: Chu
authors.forename: K E
authors.initials: KE
authors.lastname: Pollok
authors.forename: J
authors.initials: J
authors.lastname: Hurtado
authors.forename: W F
authors.initials: WF
authors.lastname: Wade
authors.forename: B S
authors.initials: BS
authors.lastname: Kwon
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000069594:Abatacept; D000469:Alkaline Phosphatase / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D005260:Female; D018796:Immunoconjugates; D008024:Ligands; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D053330:4-1BB Ligand; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008024:Ligands; D017475:Receptors, Nerve Growth Factor; C505975:Tnfsf9 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept; D000242:Cyclic AMP; D000469:Alkaline Phosphatase