The ζ Isoform of Diacylglycerol Kinase Plays a Predominant Role in Regulatory T Cell Development and TCR-Mediated Ras Signaling

Abstract

Diacylglycerol (DAG) is a critical second messenger that mediates T cell receptor (TCR)–stimulated signaling. The abundance of DAG is reduced by the diacylglycerol kinases (DGKs), which catalyze the conversion of DAG to phosphatidic acid (PA) and thus inhibit DAG-mediated signaling. In T cells, the predominant DGK isoforms are DGKα and DGKζ, and deletion of the genes encoding either isoform enhances DAG-mediated signaling. We found that DGKζ, but not DGKα, suppressed the development of natural regulatory T (Treg) cells and predominantly mediated Ras and Akt signaling downstream of the TCR. The differential functions of DGKα and DGKζ were not attributable to differences in protein abundance in T cells or in their localization to the contact sites between T cells and antigen-presenting cells. RasGRP1, a key DAG-mediated activator of Ras signaling, associated to a greater extent with DGKζ than with DGKα; however, in silico modeling of TCR-stimulated Ras activation suggested that a difference in RasGRP1 binding affinity was not sufficient to cause differences in the functions of each DGK isoform. Rather, the model suggested that a greater catalytic rate for DGKζ than for DGKα might lead to DGKζ exhibiting increased suppression of Ras-mediated signals compared to DGKα. Consistent with this notion, experimental studies demonstrated that DGKζ was more effective than DGKα at catalyzing the metabolism of DAG to PA after TCR stimulation. The enhanced effective enzymatic production of PA by DGKζ is therefore one possible mechanism underlying the dominant functions of DGKζ in modulating Treg cell development.

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

“…3). Several reports also pointed to differences in Treg signaling architecture, such as a different involvement of PKC-Θ (18), DGKζ (19), SHIP (20), or Dlgh1 (21). Finally, there have been reports that signaling intensity downstream of TCR engagement is reduced in Treg relative to Tconv cells (22)(23)(24).…”

Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

“…Whereas initial analyses reported a similar hyperactive phenotype in T cells from DGKa-and DGKz-deficient mice, a study suggests a dominant role for DGKz in suppressing the Ras signaling pathway (45). The dominant role of DGKz does not extend to other pathways; for example, DGKa-and DGKz-deficient T cells show a similar increase in the PKCq-dependent phosphorylation of IkBa (Fig.…”

“…Joshi et al (45) suggested that although DGKz is less abundant than DGKa in T cells, it has higher affinity for RasGRP1. This difference contrasts with a mathematical model that characterizes the RasGRP1 and SOS pathways as analog and digital determinants, respectively, in the regulation of Ras activation in T cells (46).…”

“…Two studies identified DGKz as being critical for the development of natural T reg (nT reg ) cells (45,68). nT reg cells contribute to peripheral T cell tolerance by limiting the responses of effector T cells, at least in part through the secretion of immunosuppressive cytokines, such as transforming growth factor-b (TGF-b) and IL-10 (69).…”

Editorial: Tweaking T cell receptor signaling thresholds through DAG: the role of diacylglycerol kinase ζ in T cell responses to TGF-β

“…Consistent with this, a loss of DGKz results in enhanced T cell responsiveness [6], supporting the hypothesis that DAG levels are involved in setting thresholds for productive T cell activation. Curiously, DGKz prevents the development of T regs within the thymus, demonstrating that this DGK plays a pivotal role in the balance between inflammation and immune tolerance [7]. The balance between inflammation and tolerance is obviously important for the prevention of autoimmunity and allograft rejection, but recent focus on the tumor microenvironment has led to the revelation that tumors evade immune clearance by tipping this balance toward tolerance.…”