CD40 on B cells and on dendritic cells mediates experimental autoimmune encephalomyelitis pathogenesis through distinct and complementary mechanisms

Abstract Costimulatory CD40 plays an essential role in autoimmune disease models including experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). However, the mechanism underlying CD40 function are not well defined in these processes. Conditional knockout of CD40 on either dendritic cells (DCs) or B cells led to profoundly reduced severity of EAE induced by recombinant human MOG (rhMOG). CD40 expression on DCs, but not on B cells, was required for priming of pathogenic T helper (Th) cells in peripheral draining lymph nodes and for appearance of these pathogenic T cells in the CNS. In marked contrast, CD40 on B cells, but not on DCs, was essential for class-switched MOG-specific antibody production. The distinct function of CD40 on B cells and DC was confirmed by the ability of transferred MOG-immune serum to restore sensitivity to EAE in mice lacking CD40 on B cells but not in mice lacking CD40 on DC. Thus, CD40 expressed on B cells and on DC provides distinct and complementary pathways essential for EAE pathogenesis, providing multiple targets for intervention in EAE, and potentially for MS and other autoimmune diseases.