Role of Diacylglycerol Kinases in T Cell Development and Function

Diacylglycerol (DAG), a second messenger generated by phospholipase C gamma 1 activity upon engagement of a T-cell receptor, triggers several signaling cascades that play important roles in T cell development and function. A family of enzymes called DAG kinases (DGKs) catalyzes the phosphorylation of DAG to phosphatidic acid, acting as a braking mechanism that terminates DAG-mediated signals. Two DGK isoforms, alpha and zeta, are expressed predominantly in T cells and synergistically regulate the development of both conventional alpha beta T cells and invariant natural killer T cells in the thymus. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T-cell hyperactivation upon T cell receptor stimulation and by promoting T-cell anergy. In CD8 cells, reduced DGK activity is associated with enhanced primary responses against viruses and tumors. Recent work also has established an important role for DGK activity at the immune synapse and identified partners that modulate DGK function. In addition, emerging evidence points to previously unappreciated roles for DGK function in directional secretion and T-cell adhesion. This review describes the multitude of roles played by DGKs in T cell development and function and emphasizes recent advances in the field.