Phosphodiesterase 7A-Deficient Mice Have Functional T Cells

Abstract

Phosphodiesterases (PDEs) are enzymes which hydrolyze the cyclic nucleotide second messengers, cAMP and cGMP. In leukocytes, PDEs are responsible for depletion of cAMP which broadly suppresses cell functions and cellular responses to many activation stimuli. PDE7A has been proposed to be essential for T lymphocyte activation based on its induction during cell activation and the suppression of proliferation and IL-2 production observed following inhibition of PDE7A expression using a PDE7A antisense oligonucleotide. These observations have led to the suggestion that selective PDE7 inhibitors could be useful in the treatment of T cell-mediated autoimmune diseases. In the present report, we have used targeted gene disruption to examine the role PDE7A plays in T cell activation. In our studies, PDE7A knockout mice (PDE7A−/−) showed no deficiencies in T cell proliferation or Th1- and Th2-cytokine production driven by CD3 and CD28 costimulation. Unexpectedly, the Ab response to the T cell-dependent Ag, keyhole limpet hemocyanin, in the PDE7A−/− mice was found to be significantly elevated. The results from our studies strongly support the notion that PDE7A is not essential for T cell activation.

TCR- and CD28-Mediated Recruitment of Phosphodiesterase 4 to Lipid Rafts Potentiates TCR Signaling

“…PDE7 has been suggested to be important for T cell proliferation with its expression up-regulated during the first 8 h of T cell activation. However, it is absent from resting T cells (65) and T cell functioning has recently been shown to be normal in knockout mice (66), indicating that PDE7 is unlikely to be involved in the regulation of the initial T cell signaling events.…”

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

“…Pharmacology/Function. A great deal of effort from the pharmaceutical industry has been invested in developing PDE7 selective inhibitors (Yang et al, 2003;Smith et al, 2004;Castro et al, 2005;Lugnier, 2005). These inhibitors and some genetic knockout technologies have been used to probe the function of PDE7 in cells and whole animals.…”

“…Despite the discovery of PDE7 more than a decade ago, until recently very few PDE7 selective inhibitors had been reported. Now, several compounds have been described, including BRL 50481 (Smith et al, 2004) and BMS-586353 (Yang et al, 2003), that have been used for in vitro pharmacological testing. Unfortunately, none are commercially available yet.…”

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

“…To complete the findings from the previous PDE7A study [22] and to directly examine the role of the second PDE7 isoform, we generated PDE7B-/-mice ( fig. 1a).…”

“…Furthermore, a PDE7A-specific antisense oligonucleotide, which blocks the expression of PDE7A, inhibits T-cell proliferation and interleukin (IL)-2 production. Although these data suggest that PDE7A plays a crucial role in T-cell activation, there are conflicting findings: for instance, PDE7A knockout (KO) mice showed no deficiency in T-cell proliferation or cytokine production driven by CD3/CD28 co-stimulation [22].…”