MOUSE INTERLEUKIN-2 RECEPTOR-ALPHA GENE-EXPRESSION - DELIMITATION OF CIS-ACTING REGULATORY ELEMENTS IN TRANSGENIC MICE AND BY MAPPING OF DNASE-I HYPERSENSITIVE SITES

The alpha chain of the interleukin-2 receptor (IL-2R alpha) is a key r egulator of lymphocyte proliferation, To analyze the mechanisms contro lling its expression in normal cells, we used the 5'-flanking region ( base pairs -2539/+93) of the mouse gene to drive chloramphenicol acety ltransferase expression in four transgenic mouse lines, Constitutive t ransgene activity was restricted to lymphoid organs, In mature T lymph ocytes, transgene and endogenous IL-2R alpha gene expression was stimu lated by concanavalin A and up regulated by IL-2 with very similar kin etics, In thymic T cell precursors, IL-1 and IL-2 cooperatively induce d transgene and IL-2R alpha gene expression, These results show that r egulation of the endogenous IL-2R alpha gene occurs mainly at the tran scrip tional level, They demonstrate that cis-acting elements in the 5 '-flanking region present in the transgene confer correct tissue speci ficity and inducible expression in mature T cells and their precursors in response to antigen, IL-1, and IL-2, In a complementary approach, we screened the 5' end of the endogenous IL-2R alpha gene for DNase-I hypersensitive sites, We found three lymphocyte specific DNase-I hyper sensitive sites. Two, at -0.05 and -5.3 kilobase pairs, are present in resting T cells, A third site appears at -1.35 kilobase pairs in acti vated T cells, It co-localizes with IL-2-responsive elements identifie d by transient transfection experiments.