The C-type lectin receptor DCIR senses galactose-terminated N-glycans on LRP1 to regulate myeloid cell function

The dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed in myeloid cells. Although patient and experimental data implicates DCIR in diverse diseases, including chronic inflammation, autoimmunity, allergy, infection, and cancer, the physiological ligand of DCIR remains elusive, leaving both its precise role in immunoregulation and its potential for therapeutic targeting unclear. Here, we identify the low-density lipoprotein receptor-related protein 1 (LRP1), a ubiquitously expressed, highly glycosylated membrane receptor, as a conserved endogenous ligand for human DCIR and murine DCIR1. DCIR specifically interacts with LRP1 through galactose-terminated biantennary complex-type N-glycans. By combining X-ray crystallography, small angle X-ray scattering, and site-directed mutagenesis, we define the structural organization of DCIR as a dimeric receptor and the basis of DCIR-glycan recognition, revealing key contact residues and an atypical glycan-binding mode. We further demonstrate that DCIR is activated through cis-interactions with its ligand upon co-engagement of ITAM-containing receptors, such as Dectin-1 or FcγRs, and modulates FcγR-mediated phagocytosis. Overall, our study addresses a long-standing gap by identifying the physiological ligand of DCIR, uncovering a novel glyco-immune recognition axis, and opening avenues for targeted intervention in DCIR-associated diseases.