Disruption of diacylglycerol metabolism impairs the induction of T cell anergy

Nat Immunol. 2006 Nov;7(11):1174-81. doi: 10.1038/ni1400. Epub 2006 Oct 8.


Anergic T cells have altered diacylglycerol metabolism, but whether that altered metabolism has a causative function in the induction of T cell anergy is not apparent. To test the importance of diacylglycerol metabolism in T cell anergy, we manipulated diacylglycerol kinases (DGKs), which are enzymes that terminate diacylglycerol-dependent signaling. Overexpression of DGK-alpha resulted in a defect in T cell receptor signaling that is characteristic of anergy. We generated DGK-alpha-deficient mice and found that DGK-alpha-deficient T cells had more diacylglycerol-dependent T cell receptor signaling. In vivo anergy induction was impaired in DGK-alpha-deficient mice. When stimulated in anergy-producing conditions, T cells lacking DGK-alpha or DGK-zeta proliferated and produced interleukin 2. Pharmacological inhibition of DGK-alpha activity in DGK-zeta-deficient T cells that received an anergizing stimulus proliferated similarly to wild-type T cells that received CD28 costimulation and prevented anergy induction. Our findings suggest that regulation of diacylglycerol metabolism is critical in determining whether activation or anergy ensues after T cell receptor stimulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Clonal Anergy / immunology*
  • Diacylglycerol Kinase / deficiency
  • Diacylglycerol Kinase / genetics
  • Diglycerides / metabolism*
  • Diglycerides / physiology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology*


  • Diglycerides
  • Receptors, Antigen, T-Cell
  • Diacylglycerol Kinase