title: Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses.
abstract: Our present study provides evidence that the 4-1BB signal is critical to CD28 co-stimulation in maintaining T cell activation when CD28 has been down-regulated because of repeated stimulation. The 4-1BB signal synergized with CD28 co-stimulation by lowering the threshold of anti-CD28 required to sustain proliferation and IL-2 production. The 4-1BB signal also modulated CD28-mediated cytokine profiles by markedly enhancing Th1 but suppressing Th2-type cytokine production. The 4-1BB signal generated Th1-type cells, as identified by intracellular IFN-gamma production. IFN-gamma induction was detected preferentially in 4-1BB-expressing cells, but not in those expressing CD30. 4-1BB and CD30 were induced in both CD4+ and CD8+ cells, but the location of the two molecules was mutually exclusive in each T cell subset. Our study suggests that the 4-1BB signal regulates CD28 co-stimulation in the targeted subset cells to favor Th1 development and maintain long-term cell growth.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: P
authors.initials: P
authors.lastname: Mantel
authors.forename: B S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D015703:Antigens, CD; D018106:CD28 Antigens / Q000502:physiology*; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D017730:Ki-1 Antigen / Q000032:analysis; D008213:Lymphocyte Activation; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D016196:S Phase; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D015703:Antigens, CD; D018106:CD28 Antigens; D016207:Cytokines; D017730:Ki-1 Antigen; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D015847:Interleukin-4; D007371:Interferon-gamma