title: Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse.
abstract: Polarization of the T cell microtubule-organizing center (MTOC) to the immunological synapse between the T cell and an antigen-presenting cell (APC) maintains the specificity of T cell effector responses by enabling directional secretion toward the APC. The reorientation of the MTOC is guided by a sharp gradient of the second messenger diacylglycerol (DAG), which is centered at the immunological synapse. We used a single-cell photoactivation approach to demonstrate that diacylglycerol kinase α (DGK-α), which catalyzes the conversion of DAG to phosphatidic acid, determined T cell polarity by limiting the diffusion of DAG. DGK-α-deficient T cells exhibited enlarged accumulations of DAG at the immunological synapse, as well as impaired reorientation of the MTOC. In contrast, T cells lacking the related isoform DGK-ζ did not display polarization defects. We also found that DGK-α localized preferentially to the periphery of the immunological synapse, suggesting that it constrained the area over which DAG accumulated. Phosphoinositide 3-kinase activity was required for the peripheral localization pattern of DGK-α, which suggests a link between DAG and phosphatidylinositol signaling during T cell activation. These results reveal a previously unappreciated function of DGK-α and provide insight into the mechanisms that determine lymphocyte polarity.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Chauveau
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Floc'h
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Niels S
authors.initials: NS
authors.lastname: Bantilan
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. husem@mskcc.org.
authors.forename: Morgan
authors.initials: M
authors.lastname: Huse
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D016764:Cell Polarity / Q000276:immunology*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007091:Image Processing, Computer-Assisted; D054992:Immunological Synapses / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D022101:Microtubule-Organizing Center / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059010:Single-Cell Analysis; D018709:Statistics, Nonparametric
chemical_list: D004075:Diglycerides; D019869:Phosphatidylinositol 3-Kinases; D019852:Diacylglycerol Kinase