Microenvironment and Immunology Interferon-a Suppresses cAMP to DisarmHuman Regulatory T Cells

IFN-a is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immuneand autoimmune-stimulating activity. However, themechanisms of immune activation by IFN-a remain incompletely understood, particularly with regard to CD4þCD25highFoxpþ regulatory T cells (Treg). Here, we show that IFN-a deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-a–mediated Treg inactivation increased CD4þ effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-a–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-a 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-a–treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-a–dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-a activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-a treatment in patients with cancer and suggests IFN-a for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens. Cancer Res; 73(18); 5647–56. 2013 AACR.