title: CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer.
abstract: Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen-presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Using a quantitative imaging-based assay, we show that the PI3K activity at the T cell-APC contact area is dependent on the p110delta, but not the p110gamma, isoform of PI3K. CD28 enhanced PIP3 production at the T-cell synapse independently of its YMNM PI3K-recruitment motif that instead was required for efficient PKC recruitment. CD28 could partially compensate for the lack of p110delta activity during T-cell activation, which indicates that CD28 and p110delta act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110delta double-deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutic targeting of p110delta activity and CD28 costimulation has potent therapeutic potential.
authors.affiliation: Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Fabien
authors.initials: F
authors.lastname: Garçon
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Patton
authors.forename: Juliet L
authors.initials: JL
authors.lastname: Emery
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D019281:Dimerization; D004789:Enzyme Activation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D054377:Chemokine CXCL12; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C