The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/11/1297/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 9, November 1, 1999 1297-1308

Original Article

Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers

Jin Zhanga, Irinoulla Scordia, Mark J. Smythb, and Mathias G. Lichtenhelda
a Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136
b Cellular Cytotoxicity Laboratory, Austin Research Institute, Austin Hospital, Heidelberg, Victoria 3084, Australia

Correspondence to: Mathias G. Lichtenheld, Dept. of Microbiology and Immunology, University of Miami School of Medicine, 1600 NW 10th Ave., RMSB 3034, Miami, FL 33136. Tel:305-243-3301 Fax:305-243-4623 E-mail:mlichten{at}med.miami.edu.

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.

Key Words: cytotoxic T lymphocyte, IL-2 receptor, T cell activation, perforin, transgenic mouse


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