title: 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.
abstract: The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Shuford
authors.forename: K
authors.initials: K
authors.lastname: Klussman
authors.forename: D D
authors.initials: DD
authors.lastname: Tritchler
authors.forename: D T
authors.initials: DT
authors.lastname: Loo
authors.forename: J
authors.initials: J
authors.lastname: Chalupny
authors.forename: A W
authors.initials: AW
authors.lastname: Siadak
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Emswiler
authors.forename: H
authors.initials: H
authors.lastname: Raecho
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: T C
authors.initials: TC
authors.lastname: Pearson
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: R S
authors.initials: RS
authors.lastname: Mittler
mesh_terms: D000818:Animals; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D007111:Immunity, Cellular; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9