Disruption of diacylglycerol metabolism impairs the induction of T cell anergy.
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.
Olenchock
Benjamin A
BA
Signal Transduction Program, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Guo
Rishu
R
Carpenter
Jeffery H
JH
Jordan
Martha
M
Topham
Matthew K
MK
Koretzky
Gary A
GA
Zhong
Xiao-Ping
XP
D000818:Animals; D017635:Clonal Anergy / Q000276:immunology*; D019852:Diacylglycerol Kinase / Q000172:deficiency / Q000235:genetics; D004075:Diglycerides / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D004075:Diglycerides; D011948:Receptors, Antigen, T-Cell; D019852:Diacylglycerol Kinase