Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of type I
interferon (IFN-I) in systemic lupus erythematosus (SLE), triggered through Toll-like
receptor (TLR)-mediated recognition of nucleic acids released from dying cells.
However, relatively little is known about how TLR signaling and IFN-I production are
regulated in pDCs. Here I describe a role for integrin αvβ3 in regulating TLR responses
and IFN-I production by pDCs in mouse models. I show that αv and β3-/-
pDCs produce more IFN-I and inflammatory cytokines than controls when stimulated though TLR7 and
TLR9 in vitro and in vivo. This dysregulated TLR signaling results in activation of B
cells and promotes germinal center B cell and plasma cell expansion. Furthermore, in a
mouse model of TLR7-driven lupus-like disease, deletion of αvβ3 from pDCs causes
accelerated autoantibody production and pathology. I therefore identify a pDC-intrinsic
role for αvβ3 in regulating TLR signaling and preventing activation of autoreactive B
cells. As αvβ3 serves as a receptor for apoptotic cells and cell debris, I hypothesize that
this regulatory mechanism provides important contextual cues to pDCs and functions to
limit responses to self-derived nucleic acids.