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

Tae Yoon Park, Sung Dong Park, Jen Young Cho, Jae Seung Moon, Na Yeon Kim, Kyungsoo Park, Rho Hyun Seong, Sang Won Lee, Tomohiro Morio, Alfred L.M. Bothwell, Sang Kyou Lee

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)18673-18678
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number52
DOIs
Publication statusPublished - 2014 Dec 30

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Th17 Cells
Autoimmunity
T-Lymphocytes
Autoimmune Experimental Encephalomyelitis
Interleukin-17
Spinal Cord
Transcription Factors
Incidence
Demyelinating Diseases
Regulatory T-Lymphocytes
Cytoplasmic and Nuclear Receptors
Tretinoin
Cell Nucleus
Rheumatoid Arthritis
Therapeutics
Animal Models
Cytokines

All Science Journal Classification (ASJC) codes

  • General

Cite this

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. / RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 52. pp. 18673-18678.
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abstract = "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 na{\"i}ve 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.",
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RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 52, 30.12.2014, p. 18673-18678.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells

AU - Park, Tae Yoon

AU - Park, Sung Dong

AU - Cho, Jen Young

AU - Moon, Jae Seung

AU - Kim, Na Yeon

AU - Park, Kyungsoo

AU - Seong, Rho Hyun

AU - Lee, Sang Won

AU - Morio, Tomohiro

AU - Bothwell, Alfred L.M.

AU - Lee, Sang Kyou

PY - 2014/12/30

Y1 - 2014/12/30

N2 - 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.

AB - 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.

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