Published online before print August 3, 2006

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(Journal of Leukocyte Biology. 2006;80:880-888.)
© 2006 by Society for Leukocyte Biology

Human CD4⁺ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP

Silvia Vendetti^*,1, Mario Patrizio, Antonella Riccomi^* and Maria Teresa De Magistris^*

Departments of
^* Infectious, Parasitic and Immune-Mediated Diseases and
Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy

¹ Correspondence: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. E-mail: vendetti{at}iss.it

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-ß 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.

Key Words: T cells • suppression • cholera toxin • immunoregulation

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