Interleukin 2 receptor signaling regulates the perforin gene through signal transducer and activator of transcription (Stat)5 activation of two enhancers

Jin Zhang, Irinoulla Scordi, Mark J. Smyth, Mathias G. Lichtenheld

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Optimal T cell differentiation into effector cells with specialized functions requires the participation of cytokine receptor signals. In T helper cells, this process is controlled by chromatin changes and distal and proximal regulatory elements as well as specific transcription factors. Analogous events during cytotoxic T lymphocyte (CTL) differentiation remain to be identified. This process is known, however, to be crucially regulated by interleukin (IL)-2 receptor (R) signals. It is accompanied by the induction of perforin expression via a mechanism that does not entail proximal regulatory elements. In this report, transgenically expressed human perforin gene locus DNAs demonstrate that IL-2R signals target two IL-2- dependent enhancers ~15 and 1 kilobase upstream of the promoter. The most distal enhancer may also respond to TCR signals. In transient transfections, both enhancers required two identically spaced Stat-like elements for their activation, which was abolished by expression of a dominant negative signal transducer and activator of transcription (Stat)5 molecule, whereas a constitutively active Stat5 molecule bypassed the requirement for IL-2R signals. These results provide a molecular explanation for the activation of the perforin gene during CTL differentiation and complement the analysis of animals deficient in the activation of the IL-2R Stat signaling pathway by establishing perforin as a target gene.

Original languageEnglish (US)
Pages (from-to)1297-1307
Number of pages11
JournalJournal of Experimental Medicine
Volume190
Issue number9
DOIs
StatePublished - Nov 1 1999

Keywords

  • Cytotoxic T lymphocyte
  • IL-2 receptor
  • Perforin
  • T cell activation
  • Transgenic mouse

ASJC Scopus subject areas

  • Immunology

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