Research ArticleImmunology

Diacylglycerol Kinase ζ Limits the Generation of Natural Regulatory T Cells

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Science Signaling  26 Nov 2013:
Vol. 6, Issue 303, pp. ra101
DOI: 10.1126/scisignal.2004411

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ERK Signaling Promotes Treg Cells

When T cell precursors (thymocytes) in the thymus receive a strong signal through their T cell receptor (TCR), they develop into natural regulatory T (nTreg) cells. TCR stimulation leads to the activation of phospholipase C–γ1 (PLC-γ1) and the production of the second messenger diacylglycerol (DAG), which, in turn, activates extracellular signal–regulated kinase (ERK) signaling. In one of a pair of papers published this week, Schmidt et al. investigated nTreg cell development in mice deficient in the ζ isoform of DAG kinase (DGKζ), an enzyme that converts DAG to phosphatidic acid, thus inhibiting DAG-dependent signaling. Compared to wild-type mice, DGKζ-deficient mice generated increased numbers of nTreg cells and their precursors. The accumulation of DAG in DGKζ-deficient thymocytes resulted in enhanced ERK activation, as well as of nuclear factor κB, and the authors found a positive correlation between the extent of ERK activation and the numbers of nTreg cells produced in vivo. Together, these data suggest that DGKζ inhibits nTreg cell generation by limiting the extent to which TCR stimulation activates ERK.