Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes

PLoS Pathog. 2013 Oct;9(10):e1003650. doi: 10.1371/journal.ppat.1003650. Epub 2013 Oct 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11c Antigen / genetics
  • CD11c Antigen / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line
  • Dendritic Cells / immunology
  • Dendritic Cells / virology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / virology*
  • Gene Deletion
  • Humans
  • Immune Tolerance*
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / physiology*
  • Mice
  • Mice, Knockout
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology*
  • Virus Replication / genetics
  • Virus Replication / immunology*


  • CD11c Antigen
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase