title: IFN-α promotes rapid human Treg contraction and late Th1-like Treg decrease.
abstract: Type I IFNs are pleiotropic cytokines that exert concerted activities in the development of antiviral responses. Regulatory T cells represent a physiologic checkpoint in the balance between immunity and tolerance, requiring fine and rapid controls. Here, we show that human regulatory T cells are particularly sensitive to the sequential effects of IFN-α. First, IFN-α exerts a rapid, antiproliferative and proapoptotic effect in vitro and in vivo, as early as after 2 d of pegylated IFN/ribavirin therapy in patients with chronic hepatitis C. Such activities result in the decline, at d 2, in circulating regulatory T cell frequency and specifically of the activated regulatory T cell subset. Later, IFN-based therapy restrains the fraction of regulatory T cells that can be polarized into IFN-γ-producing Th1-like regulatory T cells known to contribute to chronic immune activation in type 1 inflammation. Indeed, Th1-like regulatory T cell frequency significantly declines after 30 d of therapy in vivo in relation to the persistent decline of relevant IL-12 sources, namely, myeloid and 6-sulfo LacNAc-expressing dendritic cells. This event is recapitulated by experiments in vitro, providing evidence that it may be attributable to the inhibitory effect of IFN-α on IL-12-induced, Th1-like regulatory T cell polarization. In summary, our results suggest that IFN-α-driven, early regulatory T cell depletion contributes to the development of antiviral immunity, ultimately resulting in the resolution of type 1 inflammation.
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pacella
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Eleonora
authors.initials: E
authors.lastname: Timperi
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Daniele
authors.initials: D
authors.lastname: Accapezzato
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Carmela
authors.initials: C
authors.lastname: Martire
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Labbadia
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza Università di Roma, Rome, Italy;
authors.forename: Eugenio N
authors.initials: EN
authors.lastname: Cavallari
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza Università di Roma, Rome, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Ettorre
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy;
authors.forename: Ludovica
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rizzo
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Martina
authors.initials: M
authors.lastname: Severa
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Coccia
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza Università di Roma, Rome, Italy; vincenzo.barnaba@uniroma1.it silvia.piconese@uniroma1.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vullo
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy vincenzo.barnaba@uniroma1.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barnaba
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy silvia.piconese@uniroma1.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Piconese
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha
keywords: IL-12; STAT; apoptosis; desensitization.