title: PI3Kδ promotes CD4(+) T-cell interactions with antigen-presenting cells by increasing LFA-1 binding to ICAM-1.
abstract: Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice.
authors.affiliation: Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Fabien
authors.initials: F
authors.lastname: Garçon
authors.affiliation: Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Klaus
authors.identifier: 0000-0002-9432-4051
authors.initials: K
authors.lastname: Okkenhaug
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D048430:Cell Shape; D058534:Class I Phosphatidylinositol 3-Kinases; D003713:Dendritic Cells / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D058534:Class I Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; C421683:Pik3cd protein, mouse