Abstract

Strong associations between systemic autoimmunity and sustained type I interferon (IFNab) production by plasmacytoid dendritic cells (pDCs) suggest that chronic exposure to TLR ligands that stimulate IFNab production may incite autoimmunity.

However, IFNab also stimulates expression of the enzyme indoleamine 2,3 dioxygenase (IDO) that blocks T cell immunity by activating Foxp3-lineage regulatory T cells (Tregs). IDO ablation accelerates spontaneous autoimmune progression in lupus-prone MRL -lpr mice and makes B6 mice susceptible to developing lupus-like syndromes following chronic exposure to apoptotic cells, indicating that IDO attenuates lupus-progression.

Systemic treatment with DNA nanoparticles induces rapid IFNab and IDO up-regulation, and activates Tregs to suppress responses to vaccines and immune-mediated arthritis. Nanoparticle cargo DNA is sensed by a small population of splenic DCs via a cytoplasmic DNA sensing pathway.

Thus the IDO pathway is a natural regulator of autoimmunity to DNA , and targeting this tolerogenic pathway may offer a novel approach to treating autoimmune syndromes such as SLE .