RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (52), p.18673-18678
• Main Authors: Park, Tae-Yoon, Park, Sung-Dong, Cho, Jen-Young, Moon, Jae-Seung, Kim, Na-Yeon, Park, Kyungsoo, Seong, Rho Hyun, Lee, Sang-Won, Morio, Tomohiro, Bothwell, Alfred L. M., Lee, Sang-Kyou
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - therapy; Autoimmune diseases; Autoimmunity; Biological Sciences; CD4-positive T-lymphocytes; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Nucleus - immunology; Cell Nucleus - pathology; Cellular differentiation; Cytokines; DNA-binding domains; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - therapy; HEK293 Cells; HeLa Cells; Humans; interleukin-17; Medical treatment; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Secretion; sequence analysis; Spinal cord; Spinal Cord - immunology; Spinal Cord - pathology; T lymphocytes; Th1 Cells - immunology; Th1 Cells - pathology; Th17 Cells - immunology; Th17 Cells - pathology; therapeutics; transcription (genetics); Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1413687112

The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 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 TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg 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 TH17 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 TH1 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 TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.