title: EBI2 is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells.
abstract: Epstein-Barr virus induced receptor 2 (EBI2), a Gαi-coupled G protein-coupled receptor, is a chemotactic receptor for B, T and dendritic cells (DC). Genetic studies have also implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) associated with autoimmune diseases, although the corollary in primary type I IFN-producing cells has not been reported. Here we demonstrate that EBI2 negatively regulates type I IFN responses in plasmacytoid DC (pDCs) and CD11b(+) myeloid cells. Activation of EBI2(-/-) pDCs and CD11b(+) cells with various TLR ligands induced elevated type I IFN production compared to wild-type cells. Moreover, in vivo challenge with endosomal TLR agonists or infection with lymphocytic choriomeningitis virus elicited more type I IFNs and proinflammatory cytokines in EBI2(-/-) mice compared to normal mice. Elevated systemic cytokines occurred despite impaired ability of EBI2-deficient pDCs and CD11b(+) cells to migrate from the blood to the spleen and peritoneal cavity under homeostatic conditions. As reported for other immune cells, pDC migration was dependent on the ligand for EBI2, 7α,25-dihydroxycholesterol. Consistent with a cell intrinsic role for EBI2, type I IFN-producing cells from EBI2-deficient mice expressed higher levels of IRF7 and IDIN genes. Together these data suggest a negative regulatory role for EBI2 in balancing TLR-mediated responses to foreign and to self nucleic acids that may precipitate autoimmunity.
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Chiang
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Johnston
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008024:Ligands; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D010529:Peritoneal Cavity; D037342:Pertussis Toxin / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C543809:Gpr183 protein, mouse; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D051193:Toll-Like Receptors; D037342:Pertussis Toxin