Function of the antigen receptor in T cell activation

The studies described here, including ours and those of others, were aimed at understanding the mechanism(s) by which the T cell antigen receptor transmits signals that result in expression of lymphokine genes. They have focused both on the proximal molecules and biochemical events that account for transmembrane signalling, as well as on the more distal nuclear regulatory events. It is now clear that the receptor is coupled to the PI pathway, apparently via conformational changes in Ti, possibly amplification by CD3, and likely a G protein. PI second messengers appear to contribute to subsequent gene expression events, but may not be required for receptor down-regulation. How these biochemical events are coupled to gene expression still remains a mystery. However, studies of the regulation of the IL-2 gene indicate that the proximal receptor-mediated events must occur continuously for 2-4 hours to support transcriptional activation of the IL-2 gene, and that protein synthesis during this time is required. Other genes, such as the proto-oncogene c-fos, become transcriptionally active within 15 minutes of receptor triggering even in the presence of protein synthesis inhibitors. Thus, coupling of the proximal biochemical events to expression of the IL-2 gene may be dependent on the induction of a regulatory protein(s). This protein(s) may act to activate the IL-2 gene via a 275 bp segment that lies upstream of the IL-2 coding region. Studies are now in progress to understand better the molecular requirements for competence in signal transduction and conversion of these signals into gene expression events.