Enhanced T cell responses due to diacylglycerol kinase ζ deficiency


Much is known about how T cell receptor (TCR) engagement leads to T cell activation; however, the mechanisms terminating TCR signaling remain less clear. Diacylglycerol, generated after TCR ligation, is essential in T cells. Its function must be controlled tightly to maintain normal T cell homeostasis. Previous studies have shown that diacylglycerol kinase ζ (DGKζ), which converts diacylglycerol to phosphatidic acid, can inhibit TCR signaling. Here we show that DGKζ-deficient T cells are hyperresponsive to TCR stimulation both ex vivo and in vivo. Furthermore, DGKζ-deficient mice mounted a more robust immune response to lymphocytic choriomeningitis virus infection than did wild-type mice. These results demonstrate the importance of DGKζ as a physiological negative regulator of TCR signaling and T cell activation.

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Figure 1: Generation of DGKζ-deficient mice by homologous recombination.
Figure 2: Immune system development.
Figure 3: Effect of DGKζ deficiency on phosphatidic acid production in T cells.
Figure 4: Enhanced Ras-ERK activation in DGKζ-deficient T cells after TCR engagement.
Figure 5: Enhanced up-regulation of activation markers in DGKζ-deficient T cells.
Figure 6: DGKζ-deficient T cells are hyperproliferative in response to TCR stimulation.
Figure 7: Enhanced homeostatic proliferation of DGKζ-deficient T cells.
Figure 8: Enhanced cellular immune responses to LCMV infection in DGKζ-deficient mice.


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We thank M. Kahn, V. Shapiro, J. Wu and S. Newbrough for manuscript critique; E. Peterson for discussions; S. Prescott and M. Topham for Ab to DGKζ; E. Myers and A. Lee for technical assistance; and C. Clendenin, C. Culpepper and P. Thayer of the Transgenic Core of the Abramson Family Cancer Research Institute at the University of Pennsylvania for assistance in generation of the targeted mice. Supported in part by a grant from the National Institutes of Health (G.A.K). M.S.J. is supported by a postdoctoral fellowship from the Cancer Research Institute. J.S.M. is supported by a grant from the American Society of Transplantation.

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Zhong, XP., Hainey, E., Olenchock, B. et al. Enhanced T cell responses due to diacylglycerol kinase ζ deficiency. Nat Immunol 4, 882–890 (2003). https://doi.org/10.1038/ni958

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