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.
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1 November 1999
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November 01 1999
Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers
Jin Zhang,
Jin Zhang
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
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Irinoulla Scordi,
Irinoulla Scordi
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
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Mark J. Smyth,
Mark J. Smyth
bCellular Cytotoxicity Laboratory, Austin Research Institute, Austin Hospital, Heidelberg, Victoria 3084, Australia
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Mathias G. Lichtenheld
Mathias G. Lichtenheld
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
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Jin Zhang
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
Irinoulla Scordi
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
Mark J. Smyth
bCellular Cytotoxicity Laboratory, Austin Research Institute, Austin Hospital, Heidelberg, Victoria 3084, Australia
Mathias G. Lichtenheld
aDepartment of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
1used in this paper: AP, activator protein; CsA, cyclosporin A; Stat, signal transducer and activator of transcription
Received:
May 27 1999
Revision Requested:
July 21 1999
Accepted:
August 23 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 1999 The Rockefeller University Press
1999
The Rockefeller University Press
J Exp Med (1999) 190 (9): 1297–1308.
Article history
Received:
May 27 1999
Revision Requested:
July 21 1999
Accepted:
August 23 1999
Citation
Jin Zhang, Irinoulla Scordi, Mark J. Smyth, Mathias G. Lichtenheld; Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers. J Exp Med 1 November 1999; 190 (9): 1297–1308. doi: https://doi.org/10.1084/jem.190.9.1297
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