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The Journal of Immunology, 2003, 171: 6414-6420.
Copyright © 2003 by The American Association of Immunologists

Phosphodiesterase 7A-Deficient Mice Have Functional T Cells

Guchen Yang1, Kim W. McIntyre, Robert M. Townsend, Henry H. Shen, William J. Pitts, John H. Dodd, Steven G. Nadler, Murray McKinnon and Andrew J. Watson

Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543

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.




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