DCIR-mediated inhibitory regulation of TLR7-MyD88 axis prevents autoimmune neuroinflammation

Encephalitogenic T cells are responsible for developing autoimmune diseases in the central nervous system (CNS), but the pathogenesis of CNS autoimmune diseases remains incompletely understood. Dendritic cell immunoreceptor (DCIR) is an inhibitory type of C-type lectin receptor that regulates the antigen presentation ability of DCs, and DCIR deficiency exacerbates autoimmune diseases. Here, we demonstrated that DCIR deficiency induced spontaneous development of experimental autoimmune encephalomyelitis (EAE)-like encephalomyelitis in 2D2 TCR transgenic mice (2D2Tg) expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor. 2D2TgDcir ^-/- Myd88 ^-/- mice negated the spontaneous development of EAE-like encephalomyelitis. Moreover, 2D2TgDcir ^-/- Tlr7 ^-/- mice developed less EAE-like encephalomyelitis. Interestingly, an endogenous ligand of TLR7, U11snRNA, was detected in the sera of 2D2TgDcir ^-/- mice and the patients of multiple sclerosis, indicating excessive DC activation by TLR7-mediated signaling in 2D2TgDcir ^-/- mice and patients with a neuronal autoimmune disease. Thus, defective DCIR overstimulates autoreactive T cells by strengthening TLR7-mediated responses, thereby exacerbating TLR7-MyD88-mediated autoimmune diseases.