Diacylglycerol Kinase in T Cell Anergy

Abstract

Defective Ras signaling contributes to T cell anergy, which occurs when T cells are presented with antigens in the absence of costimulatory signals and leads to T cells’ unresponsiveness to subsequent stimulation. T cell anergy is a key mechanism by which inappropriate immune responses are prevented. Previous work had shown that diacylglycerol (DAG)-mediated signaling was defective in anergic T cells and that abundance of the transcript encoding diacylglycerol kinase α (DGK-α) was decreased in activated T cells and increased in anergic T cells. Two groups (Zha et al . and Olenchock et al .) extend these observations and show that DGK-α, an enzyme that converts DAG to phosphatic acid, contributes to T cell anergy. Zha et al . showed that introduction of constitutively active Ras, one of the components downstream of DAG, restored T cell responsiveness [interleukin-2 (IL-2) production and mitogen-activated protein kinase (MAPK) phosphorylation] to cells previously rendered anergic. Expression of the Dgka gene was increased in anergic T cells in the system used by Zha et al ., and overexpression of DGK-α in resting T cells diminished recruitment of the Ras guanine nucleotide exchange factor RasGRP1 to the plasma membrane, decreased IL-2 production, and decreased MAPK activation in response to stimulation. Olenchock et al . used cells from Dgka −/− mice to show that T cells from these animals failed to undergo anergy in response to T cell receptor activation in the absence of costimulatory signals. Together, these two reports demonstrate a key role in DAG metabolism in promoting T cell anergy (see Mueller). What remains to be determined is how DGK activity is regulated to prevent excessive activity in cells that receive an activating signal and to promote activity in cells that receive a signal that produces anergy. Y. Zha, R. Marks, A. W. Ho, A. C. Peterson, S. Janardhan, I. Brown, K. Praveen, S. Stang, J. C. Stone, T. F. Gajewski, T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. Nat. Immunol. 7 , 1166-1173 (2006). [PubMed] B. A. Olenchock, R. Guo, J. H. Carpenter, M. Jordan, M. K. Topham, G. A. Koretzky, X.-P. Zhong, Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat. Immunol. 7 , 1174-1181 (2006). [PubMed] D. L. Mueller, Linking diacylglycerol kinase to T cell anergy. Nat. Immunol. 7 , 1132-1134 (2006). [PubMed]