RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with T_H17 cells

The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to T_H17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited T_H17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into T_H17, but not into T_H1, T_H2, or T_reg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4⁺ T cells and spinal cord-infiltrating CD4⁺ T cells, and suppress the functions of T_H17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt- TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4⁺ IL-17⁺ T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking T_H1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with T_H17 or T_H1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.