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dc.contributor.authorComerford, I.-
dc.contributor.authorLitchfield, W.-
dc.contributor.authorKara, E.-
dc.contributor.authorMcColl, S.-
dc.identifier.citationPLoS One, 2012; 7(9):1-12-
dc.description.abstractThe class IB phosphoinositide 3-kinase γ enzyme complex (PI3Kc) 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 pik3cg2/2 mice and a selective PI3Kc inhibitor, we show that PI3Kc promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg2/2 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 pik3cg2/2 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 p110c. Together, this results in suppressed autoreactive T cell responses in pik3cg2/2 mice, with more CD4+ T cells undergoing apoptosis and fewer cytokineproducing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kc 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 PI3Kc may be useful therapeutics for MS.-
dc.description.statementofresponsibilityIain Comerford, Wendel Litchfield, Ervin Kara and Shaun R. McColl-
dc.publisherPublic Library of Science-
dc.rights© 2012 Comerford et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.-
dc.subjectCentral Nervous System-
dc.subjectDendritic Cells-
dc.subjectCD4-Positive T-Lymphocytes-
dc.subjectTh1 Cells-
dc.subjectCD8-Positive T-Lymphocytes-
dc.subjectMice, Inbred C57BL-
dc.subjectEncephalomyelitis, Autoimmune, Experimental-
dc.subjectProtein Kinase Inhibitors-
dc.subjectAdministration, Oral-
dc.subjectSignal Transduction-
dc.subjectCell Movement-
dc.subjectCell Survival-
dc.subjectGene Deletion-
dc.subjectTh17 Cells-
dc.subjectClass Ib Phosphatidylinositol 3-Kinase-
dc.titlePI3Kγ drives priming and survival of autoreactive CD4⁺ T cells during experimental autoimmune encephalomyelitis-
dc.title.alternativePI3Kgamma drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis-
dc.typeJournal article-
dc.identifier.orcidMcColl, S. [0000-0003-0949-4660]-
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Molecular and Biomedical Science publications

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