title: 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy.
abstract: A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily involved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated costimulation during a primary response to peptide Ag. 4-1BBL enhanced proliferation, cytokine production, and CTL effector function of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under similar conditions of antigenic stimulation, we performed MLRs with purified CD4 or CD8 responders from CD28(+/+) and CD28(-/-) mice. We found that CD8 T cells produced IL-2 and IFN-gamma in a 4-1BBL-dependent manner, whereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4 and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited enhanced proliferation and earlier cell division when stimulated with anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subsets responded comparably to anti-CD3 plus 4-1BBL. These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
authors.forename: J L
authors.initials: JL
authors.lastname: Cannons
authors.forename: P
authors.initials: P
authors.lastname: Lau
authors.forename: B
authors.initials: B
authors.lastname: Ghumman
authors.forename: M A
authors.initials: MA
authors.lastname: DeBenedette
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D007399:Interphase / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D018106:CD28 Antigens; D017252:CD3 Complex; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D008024:Ligands; C111390:OVA 323-339; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; C505975:Tnfsf9 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D010047:Ovalbumin