Integrin αvβ3 limits Toll-like receptor type I interferon production by plasmacytoid dendritic cells and restricts autoimmunity

Abstract

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.