Disruption of diacylglycerol metabolism impairs the induction of T cell anergy

Benjamin A Olenchock^1, 6, Rishu Guo^2, 6, Jeffery H Carpenter², Martha Jordan¹, Matthew K Topham³, Gary A Koretzky^1, 4 & Xiao-Ping Zhong^2, 5

¹  Signal Transduction Program, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

²  Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.

³  Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.

⁴  Department of Medicine, Division of Rheumatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

⁵  Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

⁶  These authors contributed equally to this work.

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- resulted in a defect in T cell receptor signaling that is characteristic of anergy. We generated DGK--deficient mice and found that DGK--deficient T cells had more diacylglycerol-dependent T cell receptor signaling. In vivo anergy induction was impaired in DGK--deficient mice. When stimulated in anergy-producing conditions, T cells lacking DGK- or DGK- proliferated and produced interleukin 2. Pharmacological inhibition of DGK- activity in DGK--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.

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