Inhibition of antigen-specific T cell proliferation and cytokine production by protein kinase A type I.
cAMP inhibits biochemical events leading to T cell activation by triggering of an inhibitory protein kinase A (PKA)-C-terminal Src kinase pathway assembled in lipid rafts. In this study, we demonstrate that activation of PKA type I by Sp-8-bromo-cAMPS (a cAMP agonist) has profound inhibitory effects on Ag-specific immune responses in peripheral effector T cells. Activation of PKA type I inhibits both cytokine production and proliferative responses in both CD4(+) and CD8(+) T cells in a concentration-dependent manner. The observed effects of cAMP appeared to occur endogenously in T cells and were not dependent on APC. The inhibition of responses was not due to apoptosis of specific T cells and was reversible by a PKA type I-selective cAMP antagonist. This supports the notion of PKA type I as a key enzyme in the negative regulation of immune responses and a potential target for inhibiting autoreactive T cells.
Aandahl
Einar Martin
EM
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94141, USA. maandahl@gladstone.ucsf.edu
Moretto
Walter J
WJ
Haslett
Patrick A
PA
Vang
Torkel
T
Bryn
Tone
T
Tasken
Kjetil
K
Nixon
Douglas F
DF
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D000242:Cyclic AMP / Q000819:agonists / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000502:physiology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology*; D004768:Enterotoxins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src); D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000942:Antigens, Bacterial; D016207:Cytokines; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma; D000242:Cyclic AMP; C086603:Matk protein, mouse; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D015232:Dinoprostone