title: Epstein-Barr virus-induced gene 3 suppresses T helper type 1, type 17 and type 2 immune responses after Trypanosoma cruzi infection and inhibits parasite replication by interfering with alternative macrophage activation.
abstract: The Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL)-12) family structurally related to the subunit p40 of IL-12 and forms a heterodimer either with the p28 subunit to build IL-27 or with p35 to form IL-35. Interleukin-27 is secreted by antigen-presenting cells whereas IL-35 appears to be produced mainly by regulatory T cells and regulatory B cells but both cytokines negatively regulate inflammatory immune responses. We here analysed the function of EBI3 during infection with the intracellular parasite Trypanosoma cruzi. Compared with C57BL/6 wild-type mice, EBI3-deficient (EBI3(-/-) ) mice showed a higher parasitaemia associated with an increased mortality rate. The EBI3(-/-) mice displayed an elevated inflammatory immune response with an increased production of T helper type 1 (Th1-), Th2- and Th17-derived cytokines. The increased Th2 immune response appears to have over-ridden the otherwise protective Th1 and Th17 immune responses by the induction of arginase-1-expressing alternatively activated macrophages in these mice. Hence, neutralization of IL-4 and arginase-1 activity partially restored protective immune responses in EBI3(-/-) mice. So far, our results demonstrate that EBI3 is an essential general regulator of inflammatory immune responses in experimental Chagas disease and is required for control of T. cruzi infection by inhibiting Th2-dependent alternative macrophage activation. Further studies are needed to dissect the underlying mechanisms and clarify whether EBI3 association with IL-27 or/and IL-35 accounts for its anti-inflammatory character in parasitic disease.
authors.affiliation: Infection Immunology, Research Centre Borstel, Borstel, Germany.|Cluster of Excellence Inflammation-at-Interfaces, Borstel-Kiel-Lübeck-Plön, Germany.|Singapore Immunology Network, Singapore, Singapore.
authors.forename: Julia
authors.initials: J
authors.lastname: Böhme
authors.affiliation: Infection Immunology, Research Centre Borstel, Borstel, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Roßnagel
authors.affiliation: Department of Immunology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jacobs
authors.affiliation: Infection Immunology, Research Centre Borstel, Borstel, Germany.|Fluorescence Cytometry Core Unit, Research Centre Borstel, Borstel, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Behrends
authors.affiliation: Infection Immunology, Research Centre Borstel, Borstel, Germany.|Cluster of Excellence Inflammation-at-Interfaces, Borstel-Kiel-Lübeck-Plön, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.affiliation: Infection Immunology, Research Centre Borstel, Borstel, Germany.|Cluster of Excellence Inflammation-at-Interfaces, Borstel-Kiel-Lübeck-Plön, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Erdmann
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D008262:Macrophage Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014349:Trypanosoma cruzi
chemical_list: C499601:Ebi3 protein, mouse; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine
keywords: alternative macrophage activation; interleukin-27; interleukin-35; parasitic infection