Negative control of diacylglycerol kinase ζ‐mediated inhibition of T cell receptor signaling by nuclear sequestration in mice

Abstract

Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)‐mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR‐induced DAG‐mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus‐cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer.

Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals

“…We have recently found that downregulation of DAG-mediated signaling and tight control DAG by DGKα/ζ is important for MAIT cell maturation. Overexpression of WT DGKζ ( Dgkz wt ) or a gain-of-function mutant of DGKζ ( Dgkz ΔNLS ) in developing thymocytes cause modest or severe inhibition of MAIT cell maturation 27 , 62 . We further examined MAIT1 and MAIT17 cell differentiation in these mice.…”

“…Masaru Taniguchi, Kim Nichols, and Luc Van Kaer. Dgkz WT -Cd4Cre and Dgkz ΔNLS - Cd4Cre mice with T cell-specific expression of WT-DGKζ or a gain-of-function DGKζ ΔNLS mutant were recently reported 27 , 62 . Primers for mouse genotyping are listed in supplementary Table 1 .…”