CCR2-dependent dendritic cell recruitment to CNS tissues during EAE promotes disease progression and inflammatory cytokine production by CNS T cells (CCR1P.243)

Abstract

Abstract Dendritic cells (DCs)—while absent from the healthy central nervous system (CNS)—rapidly accumulate within brain and spinal cord tissue during neuroinflammation associated with experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis). Yet, while DCs have been appreciated for their role in initiating adaptive immune responses in peripheral lymphoid organ tissues, how DCs infiltrate the CNS and contribute to ongoing neuroinflammation in situ is poorly understood. Therefore we sought to identify key chemokines and chemokine receptors on DCs that govern DC migration across the blood-brain barrier and within the CNS. Here we report that 1) CD11c+ bone marrow-derived (BM)DCs and CNS-infiltrating DCs express CCR2, 2) compared to CCR2+/+ cells, adoptively transferred CCR2-/- BMDCs or DC precursors do not accumulate in the CNS during EAE, despite abundance in blood, 3) CCR2-/- DCs show less accumulation in the inflamed CNS in mixed bone marrow chimeras, when compared to CCR2+/+ DCs, and 4) ablation of CCR2+/+ DCs during EAE clinical onset delays progression and attenuates T cell cytokine production. These data suggest that CCR2-dependent DC recruitment to the CNS during ongoing neuroinflammation plays a crucial role in effector T cell cytokine production and disease progression, and signify that CNS-DCs and circulating DC precursors might be key therapeutic targets for modifying ongoing neuroinflammation in CNS autoimmune diseases.