PI3K gamma is the dominant isoform involved in migratory responses of human T lymphocytes: Effects of ex vivo maintenance and limitations of non-viral delivery of siRNA
Smith, L. D., Hickman, E. S., Parry, R. V., Westwick, J. and Ward, S. G., 2007. PI3K gamma is the dominant isoform involved in migratory responses of human T lymphocytes: Effects of ex vivo maintenance and limitations of non-viral delivery of siRNA. Cellular Signalling, 19 (12), pp. 2528-2539.
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Use of mice in which individual PI3K isoforms have been deleted or mutated by gene targeting, has determined that PI3K gamma provides a key migratory signal for T lymphocyte migration. Since PI3K gamma can be a dispensable signal for directional migration of human T cells, we have adopted a pharmacological and siRNA strategy to assess the contribution of individual PI3K isoforms to chemokine-stimulated migration of human T cells. The broad spectrum PI3K isoform inhibitor Ly294002 inhibits CXCL12-stimulated migration of freshly isolated T lymphocytes. Use of second veneration inhibitors that can discriminate between individual PI3K isoforms, revealed that PI3K gamma was the major contributor to CXCL12-induced migration and PI3K/Akt signaling (as assessed by S6 phosphorylation). Non-viral delivery of siRNA targeting class I (PI3K gamma), class II (PI3KC2 alpha and PI3KC2 beta) and class III PI3Ks, followed by 3 days ex vivo culture, reduces the levels of isoform mRNA, but is insufficient to impact on cell migration responses. However, ex vivo maintenance of T cells alone, independently of siRNA treatment, resulted in the migratory response of T cells toward CXCL 12 becoming insensitive to Ly294002. Remarkably, random migration remains sensitive to Ly294002. This study therefore, highlights that the migratory response of freshly isolated human T cells is dependent on PI3K signals that are provided predominantly by PI3K gamma. However, the role of PI3K in cell migration is context-dependent and diminishes during ex vivo maintenance. (C) 2007 Elsevier Inc. All rights reserved.
|Creators||Smith, L. D., Hickman, E. S., Parry, R. V., Westwick, J. and Ward, S. G.|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
|Additional Information||ID number: ISI:000250910400012|
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