title: Regulation of Lipid Signaling by Diacylglycerol Kinases during T Cell Development and Function.
abstract: 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 Ras guanyl-releasing protein 1, PKCθ, and other effectors, whereas PA binds to effector molecules that include mechanistic target of rapamycin, Src homology region 2 domain-containing phosphatase 1, 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.
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center , Durham, NC , USA ; Department of Immunology, Duke University Medical Center , Durham, NC , USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Krishna
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
keywords: T cell activation; T cell development; T cell receptor; T cell tolerance; diacylglycerol kinase; macrophages; mast cells; phosphatidic acid