title: Costimulation of CD28- T lymphocytes by 4-1BB ligand.
abstract: The interaction of the T cell surface protein CD28 with its ligand, B7-1 or B7-2, provides a critical costimulatory signal for T cell activation. T cells from CD28- mice are deficient in a variety of responses, including those to lectins and allogeneic spleen cells. However, some immune responses do occur in CD28- mice, suggesting the existence of alternate costimulatory pathways. In this work, we show that T cells purified from CD28- mice respond to B lymphomas expressing 4-1BB ligand (4-1BBL), a member of the TNF gene family. This response is inhibited by a soluble form of 4-1BB, the T cell surface receptor for 4-1BBL. Thus, 4-1BBL/4-1BB interaction provides costimulatory signals to T cells independent of signaling through the CD28 receptor. We find that 4-1BBL is inducible on splenic B cells by CD40 ligand/CD40 interaction or by culturing of splenic dendritic cells, treatments that also induce B7 family molecules. CD28- T cells fail to respond in an MLR to resting allogeneic spleen cells. However, treatment of spleen cells with CD40 ligand renders them competent in activation of CD28- T cells. In contrast to results using B lymphomas as APC, soluble 4-1BB fails to inhibit the T cell response to activated spleen cells. This failure of soluble 4-1BB to block an MLR between CD28+ or CD28- T cells and allogeneic spleen cells is in contrast to a previous report with CD28+ cells.
authors.affiliation: Department of Immunology, University of Toronto, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: DeBenedette
authors.forename: A
authors.initials: A
authors.lastname: Shahinian
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D015703:Antigens, CD; D018106:CD28 Antigens / Q000032:analysis* / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D005260:Female; D007519:Isoantigens / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D007519:Isoantigens; D008562:Membrane Glycoproteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha