title: Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278).
abstract: To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding to ICOS peptides phosphorylated at the Y(191)MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies. However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity differentially tune up distinct ICOS signaling pathways.
authors.affiliation: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Yenny Y
authors.initials: YY
authors.lastname: Acosta
authors.forename: Maria Paz
authors.initials: MP
authors.lastname: Zafra
authors.forename: Gloria
authors.initials: G
authors.lastname: Ojeda
authors.forename: Ilaria Seren
authors.initials: IS
authors.lastname: Bernardone
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.forename: Pilar
authors.initials: P
authors.lastname: Portolés
authors.forename: Jose M
authors.initials: JM
authors.lastname: Rojo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D017931:DNA Primers; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D021122:Protein Subunits; D034741:RNA, Small Interfering; D058539:Phosphatidylinositol 3-Kinase