title: CD5 costimulation up-regulates the signaling to extracellular signal-regulated kinase activation in CD4+CD8+ thymocytes and supports their differentiation to the CD4 lineage.
abstract: CD5 positively costimulates TCR-stimulated mature T cells, whereas this molecule has been suggested to negatively regulate the activation of TCR-triggered thymocytes. We investigated the effect of CD5 costimulation on the differentiation of CD4+CD8+ thymocytes. Coligation of thymocytes with anti-CD3 and anti-CD5 induced enhanced tyrosine phosphorylation of LAT (linker for activation of T cells) and phospholipase C-gamma (PLC-gamma) compared with ligation with anti-CD3 alone. Despite increased phosphorylation of PLC-gamma, this treatment down-regulated Ca2+ influx. In contrast, the phosphorylation of LAT and enhanced association with Grb2 led to activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase. When CD3 and CD5 on CD4+CD8+ thymocytes in culture were coligated, they lost CD8, down-regulated CD4 expression, and induced CD69 expression, yielding a CD4+(dull)CD8-CD69+ population. An ERK inhibitor, PD98059, inhibited the generation of this population. The reduction of generation of CD4+CD8- cells resulted from decreased survival of these differentiating thymocytes. Consistent with this, PD98059 inhibited the anti-CD3/CD5-mediated Bcl-2 induction. These results indicate that CD5 down-regulates a branch of TCR signaling, whereas this molecule functions to support the differentiation of CD4+CD8+ thymocytes by up-regulating another branch of TCR signaling that leads to ERK activation.
authors.affiliation: Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Osaka, Japan.
authors.forename: X Y
authors.initials: XY
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.forename: K
authors.initials: K
authors.lastname: Toyo-Oka
authors.forename: C S
authors.initials: CS
authors.lastname: Park
authors.forename: X G
authors.initials: XG
authors.lastname: Tai
authors.forename: T
authors.initials: T
authors.lastname: Hamaoka
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D018956:CD5 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016827:CD8 Antigens / Q000096:biosynthesis; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D018956:CD5 Antigens; D016827:CD8 Antigens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium