title: PI3Kγ drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis.
abstract: The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kγ) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg(-/-) mice and a selective PI3Kγ inhibitor, we show that PI3Kγ promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg(-/-) mice, EAE is markedly suppressed and fewer leukocytes including CD4(+) and CD8(+) T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4(+) T cell priming in secondary lymphoid organs is reduced in pik3cg(-/-) mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110γ. Together, this results in suppressed autoreactive T cell responses in pik3cg(-/-) mice, with more CD4(+) T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kγ inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kγ may be useful therapeutics for MS.
authors.affiliation: Chemokine Biology Laboratory, the School of Molecular & Biomedical Science, the University of Adelaide, Adelaide, South Australia, Australia. iain.comerford@adelaide.edu.au
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.forename: Wendel
authors.initials: W
authors.lastname: Litchfield
authors.forename: Ervin
authors.initials: E
authors.lastname: Kara
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000378:metabolism*; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase