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

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(1). We found high Dcir expression in the joints of two mouse rheumatoid arthritis models(2-4). 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.