Journal
FRONTIERS IN IMMUNOLOGY
Volume 4, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2013.00178
Keywords
diacylglycerol kinase; phosphatidic acid; T cell development; T cell activation; T cell tolerance; T cell receptor; mast cells; macrophages
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Funding
- National Institutes of Health [AI076357, AI079088, AI101206]
- American Cancer Society [RSG-08-186-01-LIB]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI079088, R01AI076357, R01AI101206] Funding Source: NIH RePORTER
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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, PKC theta, 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, alpha and zeta, are predominantly expressed in T lineage cells and play an important role in conventional alpha beta 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.
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