Transcriptional regulation of interleukin‐2 gene expression by CD69‐generated signals

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Abstract
The 5′ flanking region of the human interleukin (IL)‐2 gene was investigated for enhancer activity in response to CD69‐generated signals, using a chloramphenicol acetyltransferase (CAT)‐driven transient expression system in Jurkat cells. The region extending from −317 to +47 relative to the initiation site of IL‐2 gene transcription was shown to contain sequences able to respond to CD69 cross‐linking, by enhancing by about 100 % a phorbol 12‐myristate 13‐acetate (PMA)‐plus‐ionomycin stimulation of CAT activity. A similar increase in CAT activity produced by PMA‐plus‐anti‐CD3 mAb was induced by CD69 cross‐linking, while a 200 % increase over that obtained by PMA‐plus‐anti‐CD28 mAb stimulation was seen. Analysis of enhancer deletion mutants revealed that proximal AP‐1, OCT‐1/octamer‐associated protein and nuclear factor of activated T cells (NFAT) binding regions were all necessary to allow CD69‐mediated enhancement of CAT activity. By gel mobility shift analysis, cyclosporin A‐sensitive NFAT‐binding induction and enhancement of AP‐1 binding activity could be detected in nuclear extracts of both Jurkat and peripheral blood T cells after simultaneous CD69 and protein kinase C stimulation. Finally, CD69‐mediated signals could increase NFAT and AP‐1 binding activity following PMA and ionomycin stimulation in peripheral blood T cells. Collectively, these data suggest that CD69‐generated signals participate in the control of the IL‐2 gene expression at the transcriptional level, likely acting through NFAT and AP‐1 transcription factor complexes.

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