T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3

Agents that increase intracellular cAMP inhibit the activation and function of T cells and can lead to cell death. Recently, it has been postulated th at cAMP inhibits T cell function in large part by acting as a brake on the T cell receptor and costimulatory receptor pathways. Therefore, for full ac tivation of the T cell to occur, this inhibitory influence must be removed. One likely mechanism for accomplishing this is by up-regulation and/or act ivation of specific cyclic nucleotide phosphodiesterases (PDEs), and such a mechanism for one phosphodiesterase, PDE7A1, has been reported. In this pa per, we extend this mechanism to another isozyme variant of the same PDE fa mily, PDE7A3. We also report the full-length sequence of human PDE8A1 and s how that it also is induced in response to a combination of T cell receptor and costimulatory receptor pathway activation. However, the time course fo r induction of PDE8A1 is slower than that of PDE7A1. The basal level measur ed and, therefore, the apparent fold induction of PDE7A1 mRNA and protein d epend in large part on the method of isolation of the T cells. On the other hand, regardless of the isolation method, the basal levels of PDE7A3 and P DE8A1 are very low and fold activation is much higher. Constitutively expre ssed PDE8A1 and PDE7A3 also have been isolated from a human T cell line, Hu t78.