title: A novel regulatory macrophage induced by a helminth molecule instructs IL-10 in CD4+ T cells and protects against mucosal inflammation.
abstract: Immunomodulation is a common feature of chronic helminth infections and mainly attributed to the secretion of bioactive molecules, which target and modify host immune cells. In this study, we show that the helminth immunomodulator AvCystatin, a cysteine protease inhibitor, induces a novel regulatory macrophage (Mreg; AvCystatin-Mreg), which is sufficient to mitigate major parameters of allergic airway inflammation and colitis in mice. A single adoptive transfer of AvCystatin-Mreg before allergen challenge suppressed allergen-specific IgE levels, the influx of eosinophils into the airways, local and systemic Th2 cytokine levels, and mucus production in lung bronchioles of mice, whereas increasing local and systemic IL-10 production by CD4(+) T cells. Moreover, a single administration of AvCystatin-Mreg during experimentally induced colitis strikingly reduced intestinal pathology. Phenotyping of AvCystatin-Mreg revealed increased expression of a distinct group of genes including LIGHT, sphingosine kinase 1, CCL1, arginase-1, and costimulatory molecules, CD16/32, ICAM-1, as well as PD-L1 and PD-L2. In cocultures with dendritic cells and CD4(+) T cells, AvCystatin-Mreg strongly induced the production of IL-10 in a cell-contact-independent manner. Collectively, our data identify a specific suppressive macrophage population induced by a single parasite immunomodulator, which protects against mucosal inflammation.
authors.affiliation: Zentrum für Infektionsmedizin, Institut für Immunologie, Freie Universität Berlin, 14163 Berlin, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziegler
authors.affiliation: Zentrum für Infektionsmedizin, Institut für Immunologie, Freie Universität Berlin, 14163 Berlin, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Zentrum für Infektionsmedizin, Institut für Immunologie, Freie Universität Berlin, 14163 Berlin, Germany;
authors.forename: Svenja
authors.initials: S
authors.lastname: Steinfelder
authors.affiliation: Mycotic and Parasitic Agents and Mycobacteria, Department of Infectious Disease Epidemiology, Robert Koch-Institute, 13353 Berlin, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Klotz
authors.affiliation: Zentrum für Infektionsmedizin, Institut für Immunologie, Freie Universität Berlin, 14163 Berlin, Germany;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hepworth
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology, Research Center ImmunoSciences, Charité-Campus Benjamin Franklin, 12203 Berlin, Germany; and.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Department of Molecular Parasitology, Humboldt-University Berlin, 10115 Berlin, Germany.
authors.forename: Paul-Christian
authors.initials: PC
authors.lastname: Burda
authors.affiliation: Department of Molecular Parasitology, Humboldt-University Berlin, 10115 Berlin, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Zentrum für Infektionsmedizin, Institut für Immunologie, Freie Universität Berlin, 14163 Berlin, Germany; susanne.hartmann@fu-berlin.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hartmann
mesh_terms: D063486:Acanthocheilonema / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D018928:Immunity, Mucosal / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology / Q000517:prevention & control
chemical_list: D000947:Antigens, Helminth; C556062:IL10 protein, mouse; D007166:Immunosuppressive Agents; D016753:Interleukin-10