DGK α and ζ Activities Control T_H1 and T_H17 Cell Differentiation

CD4⁺ T helper (T_H) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How T_H differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on T_H cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired T_H1 differentiation without obviously affecting T_H2 and T_H17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted T_H1 and T_H17 differentiation in vitro and in vivo, leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of T_H17 differentiation of DGKα and ζ double-deficient CD4⁺ T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling.