Synergistic role of diacylglycerol kinases α and ζ in T cell development and self-tolerance (137.37)

Abstract Signal for the T cell receptor (TCR) plays critical roles in T cell development and function. TCR signaling can induce positive or negative selection of thymocytes, induces activation or anergy of mature T cells, and induce conventional T cell activation or regulatory T cells to suppress immune function. The mechanisms that modulate TCR signaling to direct these distinct outcomes have been poorly understood. Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA) through phosphorylation. In mammals, ten DGK isoforms have been identified. Using both a gain of function and a loss of function approaches, we have found that DGK ( and ( are important regulators for T cells. Enhanced DGK activity inhibits TCR signaling and T cell maturation. Deficiency of either DGK( or ( causes T cells hyperresponsive to TCR stimulation and resistant to anergy induction. Loss of both DGK( and ( in mice results in impairment of positive selection, spontaneous T cell activation, impairment of regulatory T cell function, and autoimmunity. We further demonstrate that DGKs function both as signal terminator by inhibiting DAG-mediated signaling and as signaling initiator by generating PA.