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.

Author Summary

Autoimmune diabetes in humans is linked to infection with viruses, which carry cross-reactive antigens. Virus derived cross-reactive antigens break immunological tolerance to pancreatic islets, which initiates disease. Several other non-viral sources of cross-reactive antigens are known, however they usually fail to induce diabetes. Here we found that viral antigen underwent an Usp18 dependent replication in dendritic cells. This mechanism was essential to generate sufficient amounts of cross-reactive antigen and to expand autoreactive CD8 ⁺ T cells. Blocking of virus replication by either depletion of dendritic cells, genetic depletion of Usp18 or pharmacological inhibition of replication blunted expansion of autoreactive CD8 ⁺ T cells and prevented diabetes. In conclusion we found that enforced virus replication broke the tolerance to self-antigen, which partially explains the strong association of autoimmune diseases with virus infections.