Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB₁ on neurons and CB₂ on autoreactive T cells

The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB₁ and CB₂ cannabinoid receptors in regulating CNS autoimmunity. We found that CB₁ receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB₂ receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB₂-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB₂ receptor.