Phosphodiesterase 7A-deficient mice have functional T cells.
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.
Yang
Guchen
G
Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. guchen.yang@bms.com
McIntyre
Kim W
KW
Townsend
Robert M
RM
Shen
Henry H
HH
Pitts
William J
WJ
Dodd
John H
JH
Nadler
Steven G
SG
McKinnon
Murray
M
Watson
Andrew J
AJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology*; D014158:Transcription, Genetic
D007074:Immunoglobulin G; D007527:Isoenzymes; D006433:Hemocyanins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse; C032808:keyhole-limpet hemocyanin