Dysregulation of TLR9 in neonates leads to fatal inflammatory disease driven by IFN-γ

Abstract

Significance Toll-like receptors (TLRs) sense and respond to foreign nucleic acids, but this specificity raises the risk of inappropriate responses to self-nucleic acids, leading to autoimmune diseases. Limiting TLR9 activation to endosomes is thought to reduce recognition of self-DNA. To test the importance of this compartmentalized activation for immune tolerance, we developed mice with inducible expression of a mutated TLR9 that bypasses the requirement for endosomal activation. While induction of expression in adults resulted in rather mild disease, expression during development resulted in neonatal fatality dependent on type II interferon (IFN) signaling and driven by macrophages and IFN-γ–producing natural killer cells. This study uses a new model to reveal unique aspects of TLR9-driven inflammatory disease, especially early in life.