title: Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms.
abstract: PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining knowledge about the contribution of the different isoforms to PI3K function will allow selecting the most appropriate inhibitor for each pathology. In this study, we have addressed the effect of PI3K inhibitors with specificity for different class I PI3K isoforms on primary human T cell activation. In particular, we have analyzed proliferation, expression of activation and differentiation markers, apoptosis induction, cytokine secretion and Akt phosphorylation in T cells stimulated in vitro with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either one of these compounds: p110β-specific inhibitor TGX-221, p110δ-specific inhibitor IC-87114, p110γ inhibitor AS-242525 or pan-class I PI3K inhibitor BKM120. Inhibition of any of the isoforms led to an impairment of T cell activation, mainly of cytokine secretion and granzyme B expression. However, only complete blockade of class I PI3K activity with the pan-class I inhibitor effectively abrogated T cell proliferation. These results indicate that these three p110 isoforms (β, δ and γ) take part in T cell activation, but all of them are dispensable for T cell proliferation.
authors: Servicio de Hematología, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente, s/n., 37007, Salamanca, Spain, bblancod@saludcastillayleon.es.
authors: Belén
authors: B
authors: Blanco
authors: M Carmen
authors: MC
authors: Herrero-Sánchez
authors: Concepción
authors: C
authors: Rodríguez-Serrano
authors: Mercedes
authors: M
authors: Sánchez-Barba
authors: M Consuelo
authors: MC
authors: Del Cañizo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology*; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C477872:IC 87114; D007527:Isoenzymes; D009025:Morpholines; D011744:Pyrimidinones; D011799:Quinazolines; C504718:TGX 221; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000225:Adenine