Role of diacylglycerol kinases in T cell development and function

Abstract

Diacylglycerol (DAG), a second messenger generated by phospholipase Cγ1 activity upon engagement of a T-cell receptor, triggers several signaling cascades that play important roles in T cell development and function. A family of enzymes called DAG kinases (DGKs) catalyzes the phosphorylation of DAG to phosphatidic acid, acting as a braking mechanism that terminates DAG-mediated signals. Two DGK isoforms, α and ζ, are expressed predominantly in T cells and synergistically regulate the development of both conventional αβ T cells and invariant natural killer T cells in the thymus. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T-cell hyperactivation upon T cell receptor stimulation and by promoting T-cell anergy. In CD8 cells, reduced DGK activity is associated with enhanced primary responses against viruses and tumors. Recent work also has established an important role for DGK activity at the immune synapse and identified partners that modulate DGK function. In addition, emerging evidence points to previously unappreciated roles for DGK function in directional secretion and T-cell adhesion. This review describes the multitude of roles played by DGKs in T cell development and function and emphasizes recent advances in the field.

Figure 1. Structure-based classification of mammalian DGK isoforms

Based on the presence of certain structural features, mammalian DGK isoforms are classified into five types. The DGK catalytic domain consists of a conserved motif (shown with double lines) and an accessory domain (shown with a single line). RVH – recoverin homology domain, EF – EF hand, C1- cysteine-rich DAG-binding domain, PH – plextrin homology domain, SAM – sterile alpha motif, P/E- proline/glutamate-rich region, MARCKS – myristoylated alanine-rich C kinase substrate domain, A – ankyrin repeat motif, PBM – PDZ binding motif, G/P – glycine/proline-rich region.

Figure 2. DAG-mediated pathways in T cell receptor signaling

Schematic representation of various signaling pathways activated upon engagement of the T cell receptor and the CD28 co-stimulatory receptor, with an emphasis on DAG-mediated pathways. Please see the text for further details.

Figure 3. DGKs in T cell development and function

Schematic summary of the numerous roles played by DGK α and ζ in T cell development and function. In the thymus, these two DGK isoforms synergistically promote the development of conventional αβT cells and invariant NKT cells. DGK activity in mature peripheral T cells prevents their hyper-activation upon TCR engagement in the presence of co-stimulatory signals. On the other hand, DGK isoforms are highly expressed in anergic T cells and studies have revealed a critical role for DGK isoforms, particularly DGKα, in promoting T cell anergy. In CD8 cells, DGK α and ζ serve to dampen primary responses against tumor antigens and viral infection (LCMV), while promoting memory responses in the LCMV model. DGKs also play a role in establishing a stable DAG gradient that enables T cells to directionally secrete cytolytic granules and other soluble factors across the immunological synapse.