Intracellular antibody activates innate immunity (P4135)

Abstract Immune responses are initiated by infection, yet pathogens evolve faster than the host receptors tasked with their detection. Antibodies can match pathogen evolution but are extracellular whereas viruses replicate intracellularly. Recently however, we showed that viruses carry surface bound antibodies into cells when they infect. Cytosolic antibody-coated viruses are detected by the Fc-receptor and E3 ubiquitin ligase TRIM21, which targets them for proteasomal degradation in a process known as Antibody Dependent Intracellular Neutralization. Here we show that the presence of antibody in the cytosol acts as a highly potent DAMP, alerting the cell to infection and initiating an antiviral state. Upon recognition of an antibody-coated pathogen (eg a DNA or RNA non-enveloped virus or bacteria), TRIM21 synthesizes lysine-63 polyubiquitin chains and activates the NFκB, AP-1 and IRF pathways. Activation by TRIM21 is sufficient to drive production of proinflammatory cytokines, such as IL-6, TNF, CXCL10; as well as modulate surface expression of MHC Class 1-like stress ligands, such as RAE-1, H60 and HLA-E (Qa-1). In nonprofessional cells, such as primary human lung fibroblasts, TRIM21 and antibody are required for detection of adenovirus infection. In primary murine macrophages, TRIM21 mediated signalling promotes a type I immune response. The combination of intracellular antibody and ubiquitous cytosolic Fc-receptor provides a highly potent and rapidly adaptable pathogen sensor.