title: In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity.
abstract: Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3(+) regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti-IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene-induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1-treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ-producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4(+)Foxp3(+) Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Asmaa
authors.initials: A
authors.lastname: El Beidaq
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Christopher W M
authors.initials: CW
authors.lastname: Link
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Britta
authors.initials: B
authors.lastname: Frehse
authors.affiliation: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany; and.
authors.forename: Katja
authors.identifier: 0000-0002-3855-6683
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Allergy Research Group, Department of Dermatology, Medical Center, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Stefan F
authors.identifier: 0000-0002-1617-1280
authors.initials: SF
authors.lastname: Martin
authors.affiliation: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany; and.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany; Rudolf.Manz@uksh.de.
authors.forename: Rudolf A
authors.identifier: 0000-0003-1263-7693
authors.initials: RA
authors.lastname: Manz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003877:Dermatitis, Contact / Q000276:immunology*; D006241:Haptens / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D006241:Haptens; D007376:Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma