CD154 (CD40-ligand) has a wide variety of pleiotropic effects throughout the immune system and is critical to both cellular and humoral immunity. Cell surface and soluble CD154 are primarily expressed by activated CD4 T cells. Expression of CD154 is tightly regulated in a time-dependent manner, and, like most T cell-derived cytokines and other members of the tumor necrosis factor (TNF) superfamily, CD154 is largely regulated at the level of gene transcription. Recently, dysregulated expression of CD154 has been noted in a number of autoimmune disorders, including systemic lupus erythematosus (SLE). In addition, abnormal expression of CD154 has been hypothesized to contribute to a wider array of diseases, from atherosclerosis to Alzheimer's disease. Until recently, very little was known about the transcriptional regulation of CD154. We are exploring CD154 regulation in primary human CD4 T cells in hopes of understanding the cis- and trans-regulatory elements that control its expression in the cells that normally express CD154. Ultimately, we hope to be able to correct abnormal expression of CD154 in various disease states and to help design gene therapy vectors for treating CD154-deficient individuals with hyper-IgM syndrome.