Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells

Abstract

The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen-immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony-stimulating factor, Dcir-/- mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

“…There is in fact evidence that loci close to APLEC can regulate both arthritis and encephalomyelitis. 36,37 Nonetheless, the recent report that deletion of mouse Dcir1 influences arthritis and autoimmunity, 38 combined with our similar results regarding rat APLEC 5,6 and the association of RA with human APLEC and DCIR, 6 do point to evolutionarily conserved functions.…”

Enhanced Dendritic Cell-Induced Immune Responses Mediated by the Novel C-Type Lectin Receptor mDCAR1

“…The tissue-specific expression pattern of mDCAR1 could reflect a distinct function that is restricted to these tissues, but identification of potential ligands is required to test this hypothesis. Because single-nucleotide polymorphisms in genes of the DCIR/CD303/DCAR family, particularly DCAR1 in rats (10), are associated with a predisposition to autoimmune diseases such as rheumatoid arthritis (9,11), potential ligands of mDCAR1 could include not only foreign but also self-Ags.…”

C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells

“…DCIR is a rare case of a CLR that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail and, as such, is generally believed to mediate inhibitory signals in DCs. In line with this concept, antibody-mediated DCIR triggering in human DCs inhibits TLR-mediated production of IL-1β, IL-6, TNF, IL-12, and IFNα (10)(11)(12), and mice deficient in the DCIR homolog Dcir1 (also known as Clec4a2) show an overexuberant expansion of DCs and develop more agingassociated or experimentally induced antibody-and T cellmediated autoimmune disorders than their WT counterpart (13)(14)(15). Intriguingly, the mechanisms responsible for these phenotypes still remain poorly understood.…”

“…S1). To functionally explore the role of DCIR in antimycobacterial immunity, we sought to exploit a previously reported mouse model of DCIR (Dcir1/Clec4a2) deficiency (13,20). Because DCIR is primarily expressed in DCs (5), in particular those from lungs and in bone marrow-derived DCs (SI Appendix, Fig.…”