The Role of Diacylglycerol Kinase Isoforms in T cell Differentiation

CD8+ T cells are an important arm of adaptive immune responses critical for protection against intracellular pathogens and cancer. CD8+ T cells that recognizing tumor cells often exhibit a state of dysfunction and despite promising clinical progress in immunotherapies targeting immunoregulatory pathways, the fundamental mechanisms underlying T cell dysfunction remain poorly understood. Diacylglycerol kinases (DGK), a class of enzymes involved in the catalysis of diacylglycerol (DAG) into phosphatidic acid (PA), is critical for TIF induced T cell suppression. Deletion of DGKH enhanced the differentiation of effector T cell responses especially though the expression of IFNγ in CD8+ T cells. Increased effector cytokine production by DGKH knockdown is associated with increased expression of IL-2 receptor-alpha (CD25) and PD-1. Finally, adoptive transfer of tumor specific T cells lacking DGKH into liver tumor bearing mice resulted in increased expression of exhaustion marker TIM-3. In conclusion, we demonstrate the previously unexplored role of DGKH in CD8+ T cell effector responses and how DGKH could serve as a potential therapeutic target to potentiate anti-tumor T cell response