The role of high-mobility group I(Y) proteins in expression of IL-2 and T cell proliferation

The high-mobility group I(Y) (HMGI(Y)) family of proteins plays an importan t architectural role in chromatin and have been implicated in the control o f inducible gene expression. We have previously shown that expression of HM GI antisense RNA in Jurkat T cells inhibits the activity of the IL-2 promot er. Here we have investigated the role of HMGI(Y) in controlling IL-2 promo ter-reporter constructs as well as the endogenous IL-2 gene in both Jurkat T cells and human PBL. We found that the IL-2 promoter has numerous binding sites for HMGI(Y), which overlap or are adjacent to the known transcriptio n factor binding sites. HMGI(Y) modulates binding to the IL-2 promoter of a t least three transcription factor families, AP-1, NF-AT and NF-kappa B, By using a mutant HMGI that cannot bind to DNA but can still interact with th e transcription factors, we found that DNA binding by HMGI was not essentia l for the promotion of transcription factor binding. However, the non-DNA b inding mutant acts as a dominant negative protein in transfection assays, s uggesting that the formation of functional HMGI(Y)- containing complexes re quires DNA binding as well as protein:protein interactions. The alteration of HMGI(Y) levels affects IL-2 promoter activity not only in Jurkat T cells but also in PBL. Importantly, we also show here that expression of the end ogenous IL-2 gene as well as proliferation of PBL are affected by changes i n HMGI(Y) levels. These results demonstrate a major role for HMGI(Y) in IL- 2 expression and hence T cell proliferation.