PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex

Basole, C. P., Nguyen, R. K., Lamothe, K., Vang, A., Clark, R., Baillie, G. S. , Epstein, P. M. and Brocke, S. (2017) PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex. Cellular Signalling, 40, pp. 62-72. (doi: 10.1016/j.cellsig.2017.08.007) (PMID:28851628)

Abstract

The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation.

• Item Type: Articles
• Keywords: Autoimmunity, CD4(+) T cells, inflammation, integrins, PDE8, T cell motility.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baillie, Professor George
• Authors: Basole, C. P., Nguyen, R. K., Lamothe, K., Vang, A., Clark, R., Baillie, G. S., Epstein, P. M., and Brocke, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cellular Signalling
• Publisher: Elsevier
• ISSN: 0898-6568
• ISSN (Online): 1873-3913
• Published Online: 26 August 2017
• Copyright Holders: Copyright © 2017 Elsevier Inc.
• First Published: First published in Cellular Signalling 40:62-72
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher