title: Costimulation of human CD28- T cells by 4-1BB ligand.
abstract: The T cell surface protein CD28 provides a critical costimulatory signal for T cell activation. With age, humans accumulate increasing numbers of CD28- T cells, and this loss of CD28 expression is exacerbated certain disease states, such as HIV infection, autoimmune conditions or cancer. It is unclear whether CD28- T cells represent terminally differentiated effector cells or whether they remain sensitive to costimulation by CD28-independent pathways. Here, we demonstrate that 4-1 BB ligand can costimulate human CD28- T cells, resulting in cell division, inflammatory cytokine production, increased perforin levels, enhancement of cytolytic effector function, as well as the up-regulation of the anti-apoptotic protein Bcl-X(L). Thus, human CD28- T cells can respond to costimulatory signals and as such become attractive targets for therapeutic intervention, particularly in chronic infectious and inflammatory diseases where large numbers of these cells accumulate.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bukczynski
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000328:Adult; D000818:Animals; D015703:Antigens, CD; D018106:CD28 Antigens / Q000032:analysis*; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D012515:Mast-Cell Sarcoma / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000494:pharmacology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein
chemical_list: D053330:4-1BB Ligand; D015703:Antigens, CD; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D016207:Cytokines; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505714:TNFRSF9 protein, human; C505974:TNFSF9 protein, human; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D054353:Perforin