title: CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand.
abstract: 4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28- T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor-associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase-4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.
authors.affiliation: Department of Immunology, and Amgen Institute, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Saoulli
authors.forename: S Y
authors.initials: SY
authors.lastname: Lee
authors.forename: J L
authors.initials: JL
authors.lastname: Cannons
authors.forename: W C
authors.initials: WC
authors.lastname: Yeh
authors.forename: A
authors.initials: A
authors.lastname: Santana
authors.forename: M D
authors.initials: MD
authors.lastname: Goldstein
authors.forename: N
authors.initials: N
authors.lastname: Bangia
authors.forename: M A
authors.initials: MA
authors.lastname: DeBenedette
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: Y
authors.initials: Y
authors.lastname: Choi
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D018106:CD28 Antigens / Q000276:immunology*; D002460:Cell Line; D005822:Genetic Vectors; D007376:Interleukin-2 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017924:Nucleopolyhedroviruses; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D018106:CD28 Antigens; D007376:Interleukin-2; D008024:Ligands; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9