Research ArticleImmunology

The ζ Isoform of Diacylglycerol Kinase Plays a Predominant Role in Regulatory T Cell Development and TCR-Mediated Ras Signaling

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Science Signaling  26 Nov 2013:
Vol. 6, Issue 303, pp. ra102
DOI: 10.1126/scisignal.2004373

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Getting More Activity for Less DGK

Strong antigen-dependent activation of the T cell receptor (TCR) in thymocytes leads to the development of natural regulatory T (nTreg) cells through a pathway involving diacylglycerol (DAG). Metabolism of DAG by diacylglycerol kinases (DGKs) to generate phosphatidic acid (PA) limits DAG signaling. In the second of a pair of papers, Joshi et al. characterized the relative contributions of DGKα and DGKζ to TCR-dependent signaling. Although DGKα was more abundant than DGKζ in the cytosol and at the interface between T cells and antigen-presenting cells, only loss of DGKζ enhanced TCR signaling and increased generation of nTreg cells in mice. Mathematical modeling suggested that these results might be explained by the differential catalytic activities of the DGK isoforms, and experiments in T cells showed that DGKζ produced the greatest amounts of PA. Together, these results suggest that the relatively low abundance of DGKζ in T cells belies its importance in inhibiting TCR signaling.