title: Interferon-α suppresses cAMP to disarm human regulatory T cells.
abstract: IFN-α 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-α remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-α deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-α-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-α-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-α 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-α-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-α-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-α activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-α treatment in patients with cancer and suggests IFN-α for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens.
authors.affiliation: Authors' Affiliations: Department of Dermatology, Institute of Human Genetics, and Department of Immunology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz; and German Rheumatism Research Centre Berlin (DRFZ), Berlin, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bacher
authors.forename: Verena
authors.initials: V
authors.lastname: Raker
authors.forename: Claudia
authors.initials: C
authors.lastname: Hofmann
authors.forename: Edith
authors.initials: E
authors.lastname: Graulich
authors.forename: Melanie
authors.initials: M
authors.lastname: Schwenk
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
authors.forename: Luzie
authors.initials: L
authors.lastname: Merten
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Steinbrink
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D053645:Interleukin-2 Receptor alpha Subunit; C499308:Rag2 protein, mouse; D050791:STAT Transcription Factors; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases