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Type: Journal article
Title: PI3Kγ drives priming and survival of autoreactive CD4⁺ T cells during experimental autoimmune encephalomyelitis
Other Titles: PI3Kgamma drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis
Author: Comerford, I.
Litchfield, W.
Kara, E.
McColl, S.
Citation: PLoS One, 2012; 7(9):1-12
Publisher: Public Library of Science
Issue Date: 2012
ISSN: 1932-6203
Editor: Meuth, S.G.
Statement of
Iain Comerford, Wendel Litchfield, Ervin Kara and Shaun R. McColl
Abstract: The 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.
Keywords: Central Nervous System
Dendritic Cells
CD4-Positive T-Lymphocytes
Th1 Cells
CD8-Positive T-Lymphocytes
Mice, Inbred C57BL
Encephalomyelitis, Autoimmune, Experimental
Protein Kinase Inhibitors
Administration, Oral
Signal Transduction
Cell Movement
Cell Survival
Gene Deletion
Th17 Cells
Class Ib Phosphatidylinositol 3-Kinase
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.
DOI: 10.1371/journal.pone.0045095
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Appears in Collections:Aurora harvest 4
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Molecular and Biomedical Science publications

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