title: Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP.
abstract: We have previously shown that cholera toxin (CT) and other cAMP-elevating agents induce up-regulation of the inhibitory molecule CTLA-4 on human resting T lymphocytes. In this study, we evaluated the function of these cells. We found that purified human CD4(+) T lymphocytes pretreated with CT were able to inhibit proliferation of autologous PBMC in a dose-dependent manner. It is interesting that this phenomenon was not mediated by inhibitory cytokines such as IL-10, IL-4, or TGF-beta but was in part caused by the release of extracellular cAMP by the CD4(+) T lymphocytes. Purified CD4(+) T cells pretreated with forskolin, a transient cAMP inducer, or with dibutyryl cAMP, an analog of cAMP, did not exert suppressive functions, suggesting that a sustained production of cAMP, such as that induced by CT, was required to identify a novel regulatory function mediated by CD4(+) T cells. Our results show that CD4(+) T lymphocytes can exert regulatory functions through the release of extracellular cAMP and that the cyclic nucleotide acts as a primary messenger, which could play a biological role in the modulation of immune responses.
authors.affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome 00161, Italy. vendetti@iss.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Vendetti
authors.forename: Mario
authors.initials: M
authors.lastname: Patrizio
authors.forename: Antonella
authors.initials: A
authors.lastname: Riccomi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: De Magistris
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D002772:Cholera Toxin; D000242:Cyclic AMP