Title

The role of PDE8 and cAMP effector molecules in the selective regulation of Teff cell functions

Date of Completion

January 2010

Keywords

Biology, Cell|Health Sciences, Immunology

Degree

Ph.D.

Abstract

cAMP is the prototypical second messanger and touches upon almost every aspect of cell function. In immune regulation, it has been extensively characterized as an anti-inflammatory agent and enhancing accumulation of cAMP is a major goal of developing novel and specific treatments for inflammatory and autoimmune diseases. While the importance of cAMP signaling in immune function has been known for decades, two important questions remain unresolved. First, how are cAMP levels regulated in pathogenic effector T cells (Teff) during inflammation, and second, by which downstream mechanisms does cAMP exerts its anti-inflammatory effects. The overall goal of this thesis project is to address both of these areas in detail which will expanding the current knowledge of cAMP signaling during inflammation and hopefully, lead to the development of novel and selective treatments for autoimmune and inflammatory disorders. The first major goal of this thesis focuses on enhancing CAMP accumulation by blocking the cAMP degradation pathway. Phosphodiesterases (PDEs) are the sole cAMP degrading enzymes within a cell, and in Teff cells, PDE4 plays a prominent role, but its control of cAMP levels in Teff cells is not exclusive. We postulated that PDE8, an isoform with 40-100-fold greater affinity for cAMP than PDE4, is an important regulator of distinct Teff cell functions. Using a novel and previously untested highly PDE8-selective inhibitor, our data identify PDE8 as a novel target for suppression of left cell functions, including adhesion to endothelial cells. The second major goal of this thesis examines if protein kinase A (PKA) signaling through the transcription factor inducible cAMP early repressor (ICER) downstream of cAMP is necessary to suppress Teff function. We utilized Crem-/-ICER-deficient mice and pharmacological agents to identify PKA and ICER as redundant mediators of the suppressive action of regulatory T cells and cAMP on left cells and suggest that exchange protein activated by cAMP (Epac) may function as an altemative effector to promote cAMP dependent Teff cell suppression. ^