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Cell Signal. 2017 Dec;40:62-72. doi: 10.1016/j.cellsig.2017.08.007. Epub 2017 Aug 26.

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

Author information

1
Department of Immunology, UConn Health, United States.
2
Department of Immunology, UConn Health, United States; The National Hospital of Faroe Islands, Faroe Islands.
3
Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
4
Department of Cell Biology, UConn Health, United States.
5
Department of Immunology, UConn Health, United States. Electronic address: sbrocke@uchc.edu.

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.

KEYWORDS:

Autoimmunity; CD4(+) T cells; Inflammation; Integrins; PDE8; T cell motility

PMID:
28851628
DOI:
10.1016/j.cellsig.2017.08.007
[Indexed for MEDLINE]

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