Impact of suppressing retinoic acid‐related orphan receptor gamma t ( ROR )γt in ameliorating central nervous system autoimmunity

Summary M ultiple sclerosis ( MS ) is an immune‐mediated chronic central nervous system ( CNS ) disease affecting more than 400 000 people in the United States. Myelin‐reactive CD 4 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 CD 4 T cells for MS treatment. While suppressing T ‐bet, the key transcription factor in T helper type 1 ( T h1) 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 )γt, the key transcription factor for T h17 cells, has not been well‐characterized. In this study, we characterized the correlation between ROR γt expression and other factors affecting T cell encephalitogenicity and evaluated the therapeutic potential of targeting ROR γt by si RNA inhibition of ROR γt. Our data showed that ROR γt expression correlates with interleukin ( IL )‐17 production, but not with the encephalitogenicity of myelin‐specific CD 4 T cells. IL ‐23, a cytokine that enhances encephalitogenicity, does not enhance ROR γt expression significantly. Additionally, granulocyte–macrophage colony‐stimulating factor ( GM‐CSF ) levels, which correlate with the encephalitogenicity of different myelin‐specific CD 4 T cell populations, do not correlate with ROR γt. More importantly, inhibiting ROR γt expression in myelin‐specific CD 4 T cells with an si RNA does not reduce disease severity significantly in adoptively transferred EAE . Thus, ROR γt is unlikely to be a more effective therapeutic target for ameliorating pathogenicity of encephalitogenic CD 4 T cells.