title: Commitment of activated T cells to secondary responsiveness is enhanced by signals mediated by cAMP-dependent protein kinase A-I.
abstract: Modalities that induce specific differentiation to T cell memory in immune responses are important for vaccine design, but there is a paucity of well characterized molecular pathways useful to target for this purpose. We have shown previously that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances the commitment of in vitro allo-primed human T cells to secondary responsiveness, a characteristic crucial for memory T cells, which are key determinants of the longevity of the immune response. We now show that this effect can also be mediated by activation of adenylate cyclase (AC) and involves PDE4, but not PDE3 or PDE7. PF-mediated enhancement of T-cell priming is inhibited by blocking AC, is specifically signaled via cAMP-dependent protein kinase A (PKA) isoform I, and is probably independent of both nuclear factor-kappaB and the mitogen-activated protein kinase cascade. Furthermore, known pharmacological inhibitors of AC or PKA by themselves cannot block T-cell priming in the absence of PF or rolipram (Rm), and enhancement of priming requires the presence of PF only relatively late during a 4-day priming in vitro (at 48-96 h), suggesting that pharmacological extension of cAMP-mediated signaling can bring about an event critical for T cell commitment to memory. Furthermore, PF and Rm prevent induction of caspase activation and apoptosis in anti-CD3-activated human T cells. Together, our data suggest that PKA-I-mediated signals triggered by prolonging the half-life of cAMP induced during T-cell priming increase survival of activated T cells and enhance memory T cell commitment.
authors.affiliation: National Institute of Immunology, New Delhi, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Vig
authors.forename: Anna
authors.initials: A
authors.lastname: George
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
authors.forename: Jeannine
authors.initials: J
authors.lastname: Durdik
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
authors.forename: Vineeta
authors.initials: V
authors.lastname: Bal
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D017209:Apoptosis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D010431:Pentoxifylline / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000262:Adenylyl Cyclases; D010431:Pentoxifylline