Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions.
The diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG)-mediated signals by catalyzing the conversion of DAG to phosphatidic acid. In T lymphocytes, the antigen-stimulated generation of DAG links signal strength to the intensity and duration of signaling by the Ras-extracellular signal-regulated kinase (ERK) and protein kinase C (PKC)-dependent pathways. The generation of DAG at the plasma membrane of T cells lies at the core of the mechanisms that delimit T cell functions. DGKα and DGKζ are the two main isoforms that are found in T cells, and several approaches define their precise contribution to T cell responses. Each of these isoforms has specialized and redundant functions that limit the intensity of DAG-regulated signals downstream of antigenic stimulation. This ability, which in normal T cells contributes to maintaining homeostasis and function, is exploited by tumors to evade immune surveillance. Modification of DGK activity offers new perspectives for the therapeutic manipulation of T cell functions for treatment of autoimmune pathologies, or for overcoming tumor-induced T cell tolerance. Precise knowledge of the mechanisms that sustain DGK isoform-specific regulation in T lymphocytes is indispensable for the development of new tools for pharmacological intervention.
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, E-28049 Madrid, Spain. imerida@cnb.csic.es.
Isabel
I
Mérida
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, E-28049 Madrid, Spain.
Elena
E
Andrada
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, E-28049 Madrid, Spain.
Severine I
SI
Gharbi
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, E-28049 Madrid, Spain.
Antonia
A
Ávila-Flores
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D019852:Diacylglycerol Kinase / Q000276:immunology*; D004075:Diglycerides / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011493:Protein Kinase C / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape
D004075:Diglycerides; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases