The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (ROR...t) is a transcription factor (TF) specific to ... 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 ROR...t using cell-transducible form of transcription modulation domain of ROR...t (tROR...t-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tROR...t-TMD specifically inhibited ...-related cytokines induced by ROR...t, thereby suppressing the differentiation of naive T cells into ..., but not into ..., ..., or Treg cells. tROR...t-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 ... cells. The clinical severity and incidence of EAE were ameliorated by tROR...t-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 tROR...t-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking ... differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tROR...t-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with ... or ... This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis. (ProQuest: ... denotes formulae/symbols omitted.)