Regulation of lipid signaling by diacylglycerol kinases during T cell development and function

• Main Authors: Sruti eKrishna, Xiao-Ping eZhong
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-07-01
• Series: Frontiers in Immunology
• Subjects: Diacylglycerol Kinase; Macrophages; Mast Cells; T cell receptor; T cell activation; T cell development
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00178/full

Diacylglycerol (DAG) and phosphatidic acid (PA) are bioactive lipids synthesized when the T cell receptor binds to a cognate peptide-MHC complex. DAG triggers signaling by recruiting RasGRP1, PKCθ and other effectors, whereas PA binds to effector molecules that include mTOR, SHP1 and Raf1. While DAG-mediated pathways have been shown to play vital roles in T cell development and function, the importance of PA-mediated signals remains less clear. The diacylglycerol kinase (DGK) family of enzymes phosphorylates DAG to produce PA, serving as a molecular switch that regulates the relative levels of these critical second messengers. Two DGK isoforms, α and ζ, are predominantly expressed in T lineage cells and play an important role in conventional αβ T cell development. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T cell hyper-activation and promoting T cell anergy. In this review, we discuss the roles of DAG-mediated pathways, PA-effectors and DGKs in T cell development and function. We also highlight recent work that has uncovered previously unappreciated roles for DGK activity, for instance in invariant NKT cell development, anti-tumor and anti-viral CD8 responses, and the directional secretion of soluble effectors.