CD1d-restricted lipid antigens, or IL-12 and IL-18 activate invariant natural killer T (iNKT) cells that rapidly produce both  Th1  and Th2 cytokines. iNKT cells collected during vaso-occlusive episodes from patients with sickle cell disease displayed strong sterile activation with elevated expression of phospho-NF-kB p65 (Ser276), Tbet, IFN-γ, IL-13 as well as anti-inflammatory adenosine A_2A receptors (A_2ARs) and the ecto-ATPase CD39, that dephosphorylates extracellular  ATP and ADP. We hypothesized that induction of purinergic signaling molecules upon activation of iNKT cells gradually modifies their cytokine production. Activation of cultured human iNKT cells  with  α-CD3/α-CD28 induced mRNAs for pannexin1 and the P2X7 receptor (these molecules can dimerize to form a channel that releases ATP and NAD to the extracellular space); the equilibrative nucleoside transporter, ENT1; ecto-enzymes CD73, CD38 and CD39 (that together convert extracellular ATP or NAD to adenosine); and A_2ARs. Transcript for adenosine deaminase (ADA), which degrades adenosine, was reduced. Exposure of iNKT cells to the A_2AR agonist regadenoson, or the adenylyl cyclase activator forskolin during iNKT cell activation reduced production of IFN-γ and enhanced production of IL-13 and CD39. Based on these findings we define "purinergic cytokine bias" in activated iNKT cells as a gradual increase in the expression of purinergic signaling molecules (P2X7R/PANX1, CD38 CD39, CD73 and A2AR) and a decrease in ADA expression, to enhance ATP/NAD release and metabolism and adenosine signaling, and to increase the ratio of Th2/Th1 cytokine production. The data suggest that a coordinated purinergic response functions to limit the extent and duration of iNKT cell activation.