Diacylglycerol Kinases in T Cell Tolerance and Effector Function

Abstract

Diacylglycerol kinases (DGKs) are a family of enzymes that regulate the relative levels of diacylglycerol (DAG) and phosphatidic acid (PA) in cells by phosphorylating DAG to produce PA. Both DAG and PA are important second messengers cascading T cell receptor (TCR) signal by recruiting multiple effector molecules, such as RasGRP1, PKCθ, and mTOR. Studies have revealed important physiological functions of DGKs in the regulation of receptor signaling and the development and activation of immune cells. In this review, we will focus on recent progresses in our understanding of two DGK isoforms, α and ζ, in CD8 T effector and memory cell differentiation, regulatory T cell development and function, and invariant NKT cell development and effector lineage differentiation.

Keywords: diacylglycerol kinase; invariant NKT cells; regulatory T cells.

Figure 1

DGKα and DGKζ in T cell activation and anergy. Engagement of the TCR in the presence of co-stimulation results in strong activation of the PI3K-PDK1-Akt pathway (left panel). This pathway leads to mTORC2 signaling. Together with activation of the RasGRP1/Ras-Erk1/2 and PKCθ-CARMA1 pathways, they leads to mTORC1 activation. mTORC2 also promotes Akt activation via phosphorylation. Activated Akt phosphorylates Foxo1, leading to it sequestration in the cytosol and failure to activate DGKα transcription. In activated T cells, miR-34a is upregulated, which in turn downregulates DGKζ expression. Decreased DGKα and ζ expression leads to strong DAG-mediated signaling including increases of AP-1 and NFκB activity. AP-1 associates with NFAT to promote T cell activation. At the same time, AP-1 reduces monomeric NFAT to prevent it from inducing anergy promoting molecules. Strong DAG signaling together with IP3-CaN (calcineurin)-NFAT signaling allows full activation of T cells. In contrast, engagement of TCR in the absence of co-stimulation decreases PI3K-Akt-mTOR signaling, leading to increased nuclear Foxo1 and DGKα transcription (right panel). miR-34a mediated repression of DGKζ might also be lost under anergy inducing conditions. Increased DGKα and ζ expression may lead to a skewed balance between IP3 and DAG toward strong or selective Ca⁺⁺-NFAT signaling and induction of Egr1/2, which further induce transcription of DGKα and DGKζ as well as other anergy promoting molecules. Selective IP3-Ca⁺⁺-NFAT signaling in the presence of weak DAG-mediated signaling induces T cells to enter an anergic state.

Figure 2

Regulation of iNKT cell development by DGKα and DGKζ. CD4⁺CD8⁺ DP thymocytes expressing the iVα14TCR undergo positive selection to become iNKT cells. RasGRP1/mTOR signaling is critical for generation of stage 0 iNKT cells. Constitutive DGKα inhibits iNKT generation possibly by inhibiting RasGRP1/Erk1/2 activation. DGKα and ζ double deficiency or overactivation of IKKβ causes similar blockade of early iNKT cell development. Overactivation of mTORC1 due to TSC1 deficiency leads to blockade of iNKT terminal maturation. DGKα and ζ double deficiency or expression of a constitutively active KRas also results in impaired iNKT terminal maturation, correlated with elevated mTORC1 activation.