Differentiation of naive CD4+ T cells into CD4+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation.

Human CD4+CD25+ regulatory T (T(R)) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring T(R) cells develop in the thymus, adaptive T(R) cells develop in the periphery from naive CD4+ T cells. Adaptive T(R) cells may express cyclooxygenase type 2 (COX-2) and suppress effector T cells by a PGE(2)-dependent mechanism, which is reversible with COX inhibitors.

LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism.

Monocytes initiate innate immune responses and interact with T cells to induce antigen-specific immune responses by antigen presentation and secretion of humoral factors. We have previously shown that adaptive regulatory T cells inhibit T-cell effector functions in a cyclooxygenase (COX)-2-prostaglandin E(2) (PGE(2))-dependent manner and that PGE(2) converts resting CD4+CD25- T cells into FOXP3+ T cells with a suppressive phenotype. Here, we demonstrate that stimulation of monocytes with LPS leads to suppression of T-cell immune responses by a COX-2-PGE(2)-dependent mechanism that is reversible with COX-2 inhibitors as well as PGE(2)-neutralizing antibody and cAMP antagonist.

The cyclic AMP-Epac1-Rap1 pathway is dissociated from regulation of effector functions in monocytes but acquires immunoregulatory function in mature macrophages.

cAMP mediates its intracellular effects through activation of protein kinase A (PKA), nucleotide-gated ion channels, or exchange protein directly activated by cAMP (Epac). Although elevation of cAMP in lymphocytes leads to suppression of immune functions by a PKA-dependent mechanism, the effector mechanisms for cAMP regulation of immune functions in monocytes and macrophages are not fully understood. In this study, we demonstrate the presence of Epac1 in human peripheral blood monocytes and activation of Rap1 in response to cAMP.

Cytokine networks are pre-activated in T cells from HIV-infected patients on HAART and are under the control of cAMP.

Objective: Cytokines seem to play a critical role in HIV infection. The cAMP/protein kinase A (PKA) type I pathway is shown to be hyper-activated and contributes to T-cell immune dysfunction in HIV infection. Here, we analysed firstly the levels of cytokine gene expression in unstimulated CD3+T cells from HIV-infected patients on HAART, and secondly the regulation of cytokine and cytokine-related genes by cAMP agonist and antagonist in anti-CD3 activated T cells in order to understand their effects on cytokine networks.

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.