Abstract SLE is a chronic, systemic autoimmune disease affecting millions of people worldwide. SLE is caused by a breakdown of tolerance to self-derived nucleic acids (NA) and characterized by the presence of autoantibodies to DNA/RNA. Plasmacytoid dendritic cells (pDCs) are highly tuned to respond to NA and express a range of receptors for RNA and DNA, including TLRs 7 and 9. Following TLR engagement, pDCs produce high levels of type I interferon (IFN-I), which promotes loss of tolerance, implicating pDCs in development of autoimmunity. However, relatively little is known about how innate immune signaling is regulated in pDCs, and particularly how they distinguish self-derived from foreign NA. TLRs 7 and 9 are both localized in endosomal compartments, and their NA ligands must be internalized and processed before they can bind. One source of these NA is dying cells and loss of their receptors is associated with SLE. We studied the role of an apoptotic cell receptor, Integrin αv, in TLR signaling of pDCs and found that αv limits IFN-I production. In mice without αv, there is a systemic increase in IFN-I and inflammatory cytokines after TLR7 stimulation. This corresponds with an increase in pDC activation and the number of IFN-I-producing pDCs in the spleen. αv-knockout pDCs show increased TLR signaling and produce more IFN-I and inflammatory cytokines when stimulated in culture. These data indicate αv has a pDC-intrinsic role in limiting TLR signaling, which we propose is through activation of non-canonical autophagy. Based on these data, we hypothesize that co-receptors involved in capture and internalization of nucleic acids provide contextual ‘cues’ to regulate TLR signaling and prevent autoimmunity.