The role of diacylglycerol kinases in T cell anergy.

Engagement of the T cell antigen receptor (TCR) results in the activation of multiple biochemical second messenger cascades that must be integrated for the appropriate T cell response. Once the critical TCR-stimulated signaling pathway is initiated by activation of protein tyrosine kinases, a series of adapter proteins is recruited that brings tyrosine-phosphorylated phospholipase Cgamma1 into the vicinity of its substrate, phosphatidylinositol-4,5-bisphosphate, resulting in the formation of two second messengers, inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Previous work from multiple laboratories has shown that the balance between signals downstream of IP3 versus those downstream of DAG has profound effects on the fate of the stimulated T cells. In this report we summarize our recent data indicating that one key determinant of this balance of signals is the activity of members of the diacylglycerol kinase family, enzymes that convert DAG into phosphatidic acid.