Activation of T cells from patients with systemic lupus erythematosus (SLE) leads to increased signaling responses, detected by increased calcium and protein tyrosine phosphorylation patterns. This overexcitability occurs in spite of decreased levels of T-cell receptor ζ chain. The replacement of the ζ chain by the Fc receptor (FcR) γ chain and the formation of signaling molecule aggregates on the surface of T cells are considered to be responsible for the observed signaling phenotype. Decreased production of the ζ-chain promoter binding form of the transcription factor Elf-1 is responsible for the decreased transcription of the ζ chain gene. In addition, transcription of the interleukin-2 (IL-2) gene is decreased because of the presence of the transcriptional repressor cyclic adenine mono-phosphate (cAMP) response element modulator. Replenishment of the ζ chain and elimination of the repressor by antisense approaches leads to increased expression of IL-2, suggesting that gene therapy approaches might represent tangible modalities in the treatment of human SLE.