Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells

Jong Hyun Park, Ji Seung Ko, Yoonchul Shin, Jen Young Cho, Han Ah Oh, Alfred M. Bothwell, Sang Kyou Lee

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Regulatory T cells (Treg cells) are crucial for the maintenance of immunological tolerance, and it has been reported that Treg cells are enriched within the tumor micro-environment for immune evasion due to their immunosuppressive functions. To inhibit Treg cells functions, FoxP3, a lineage-specific transcription factor responsible for the differentiation and functions of Treg cells, was functionally targeted by a nucleus-transducible (nt) form of various FoxP3 functional subdomains. These nt modified domains can be delivered into the nucleus effectively and work as interactomic inhibitors via disruption of the endogenous FoxP3-mediated transcription complex. Among these domains, nt-FoxP3-FKH (Forkhead DNA binding domain) is most effective at restoring NFAT activity suppressed by FoxP3, and inhibiting the binding of endogenous FKH-containing proteins to FKH DNA binding sequences without influencing the viability and activation of T cells. The suppressive functions of TGF-β-induced iTreg cells and thymus-derived tTreg cells were substantially blocked by nt-FoxP3-FKH, accompanied with down-regulation of CTLA-4 surface expression and IL-10 secretion of Treg cells. In addition, nt-FoxP3-FKH upregulated the expression of IL-2 and IFN-γ in Treg cells. Therefore, nt-FoxP3-FKH has the potential to be a novel therapeutic agent to modulate the immune-evasive tumor environment created by Treg cells without the need for genetic modifications.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume451
Issue number1
DOIs
StatePublished - Aug 15 2014
Externally publishedYes

Keywords

  • Cancer immunotherapy
  • FoxP3
  • Intranuclear interactomic inhibitor of transcription factor
  • Protein transduction domain
  • Regulatory T cells

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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