Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunctions including defective interleukin-2 (IL-2) production. The fundamental underlying molecular mechanisms remain largely unknown. This laboratory has considered that deficient production of IL-2 represents decreased transcription of the IL-2 gene and has undertaken a systematic analysis to investigate aberrations of transcription factors that bind to the IL-2 promoter and cause defective IL-2 gene transcription. The presented preliminary studies show that IL-2 production by SLE T cells is decreased and the activity of two activators, nuclear factor (NF)-kappaB and activating protein (AP)-1, is decreased, whereas the activity of the repressor cAMP responsive element modulator (CREM) is increased. The latter binds to the -180 (-164/-189) site of the IL-2 promoter and suppresses gene transcription. This information suggests that the decreased IL-2 production in human SLE is the result of transcriptional repression mediated by the increased expression of CREM and/or the decreased activity of activators. This hypothesis will be addressed logically in experiments planned in 3 specific aims, which will: 1) Establish in cross-sectional and longitudinal studies that the increased expression of CREM in human SLE subjects is disease-specific and disease activity-independent and that it relates directly with the decreased production of IL-2. 2) Determine how CREM suppresses the production of IL-2 in human SLE T cells by studying its ability to interact with other transcription factors on the IL-2 promoter. 3) Investigate the mechanisms that are involved in the increased expression of CREM in SLE T cells. Defective IL-2 production contributes to increased infection-related morbidity and mortality rates in patients with SLE. The proposed studies will contribute to our understanding of the origin of a major clinical problem.