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 language | English (US) |
---|---|
Pages (from-to) | 1297-1307 |
Number of pages | 11 |
Journal | Journal of Experimental Medicine |
Volume | 190 |
Issue number | 9 |
DOIs | |
State | Published - Nov 1 1999 |
Keywords
- Cytotoxic T lymphocyte
- IL-2 receptor
- Perforin
- T cell activation
- Transgenic mouse
ASJC Scopus subject areas
- Immunology