Impact of suppressing retinoic acid-related orphan receptor gamma t (ROR)[gamma]t in ameliorating central nervous system autoimmunity

Summary Multiple sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease affecting more than 400000 people in the United States. Myelin-reactive CD4 T cells play critical roles in the formation of acute inflammatory lesions and disease progression in MS and experimental autoimmune encephalomyelitis (EAE), a well-defined mouse model for MS. Current MS therapies are only partially effective, making it necessary to develop more effective therapies that specifically target pathogenic myelin-specific CD4 T cells for MS treatment. While suppressing T-bet, the key transcription factor in T helper type 1 (Th1) cells, has been demonstrated to be beneficial in prevention and treatment of EAE, the therapeutic potential of retinoic acid-related orphan receptor gamma t (ROR)[gamma]t, the key transcription factor for Th17 cells, has not been well-characterized. In this study, we characterized the correlation between ROR[gamma]t expression and other factors affecting T cell encephalitogenicity and evaluated the therapeutic potential of targeting ROR[gamma]t by siRNA inhibition of ROR[gamma]t. Our data showed that ROR[gamma]t expression correlates with interleukin (IL)-17 production, but not with the encephalitogenicity of myelin-specific CD4 T cells. IL-23, a cytokine that enhances encephalitogenicity, does not enhance ROR[gamma]t expression significantly. Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, which correlate with the encephalitogenicity of different myelin-specific CD4 T cell populations, do not correlate with ROR[gamma]t. More importantly, inhibiting ROR[gamma]t expression in myelin-specific CD4 T cells with an siRNA does not reduce disease severity significantly in adoptively transferred EAE. Thus, ROR[gamma]t is unlikely to be a more effective therapeutic target for ameliorating pathogenicity of encephalitogenic CD4 T cells.