Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

IFN-alpha is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune-and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-alpha remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-alpha deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-alpha-mediated Treg inactivation increased CD4_ effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-alpha-induced MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphodiesterase 4 (PDE4) activation and accompanied by downregulation of IFN receptor (IFNAR)-2 and negative regulation of T-cell receptor signaling. IFN-alpha did not affect the anergic state, cytokine production, Foxp3 expression, or methylation state of the Treg-specific demethylated region (TSDR) within the FOXP3 locus associated with a stable imprinted phenotype of human Treg. Abrogated protection by IFN-alpha-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-alpha-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-alpha activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-alpha treatment in patients with cancer and suggests IFN-alpha for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens. (C) 2013 AACR.