title: Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes.
abstract: Infection with viruses carrying cross-reactive antigens is associated with break of immunological tolerance and induction of autoimmune disease. Dendritic cells play an important role in this process. However, it remains unclear why autoimmune-tolerance is broken during virus infection, but usually not during exposure to non-replicating cross-reactive antigens. Here we show that antigen derived from replicating virus but not from non-replicating sources undergoes a multiplication process in dendritic cells in spleen and lymph nodes. This enforced viral replication was dependent on Usp18 and was essential for expansion of autoreactive CD8⁺ T cells. Preventing enforced virus replication by depletion of CD11c⁺ cells, genetically deleting Usp18, or pharmacologically inhibiting of viral replication blunted the expansion of autoreactive CD8⁺ T cells and prevented autoimmune diabetes. In conclusion, Usp18-driven enforced viral replication in dendritic cells can break immunological tolerance and critically influences induction of autoimmunity.
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany ; Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Honke
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Iliakis
authors.forename: Haifeng C
authors.initials: HC
authors.lastname: Xu
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000821:virology*; D017353:Gene Deletion; D006801:Humans; D007108:Immune Tolerance; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D039521:CD11c Antigen; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase