Induction of antiinflammatory purinergic signaling in activated human iNKT cells.

Invariant natural killer T (iNKT) cells are activated at sites of local tissue injury, or globally during vaso-occlusive episodes of sickle cell disease (SCD). Tissue damage stimulates production of CD1d-restricted lipid antigens that activate iNKT cells to produce Th1- and Th2-type cytokines. Here, we show that circulating iNKT cells in SCD patients express elevated levels of the ectonucleoside triphosphate diphosphosphohydrolase, CD39, as well the adenosine A2A receptor (A2AR). We also investigated the effects of stimulating cultured human iNKT cells on the expression of genes involved in the regulation of purinergic signaling. iNKT cell stimulation caused induction of ADORA2A, P2RX7, CD38, CD39, ENPP1, CD73, PANX1, and ENT1. Transcription of ADA, which degrades adenosine, was reduced. Induction of CD39 mRNA was associated with increased ecto-ATPase activity on iNKT cells that was blocked by POM1. Exposure of iNKT cells to A2AR agonists during stimulation reduced production of IFN-γ and enhanced production of IL-13 and CD39. Based on these findings, we define "purinergic Th2-type cytokine bias" as an antiinflammatory purinergic response to iNKT cell stimulation resulting from changes in the transcription of several genes involved in purine release, extracellular metabolism, and signaling.

不变自然杀伤T（iNKT）细胞在局部组织损伤部位被激活，或在镰状细胞病（SCD）的血管闭塞发作期间全身性激活。组织损伤刺激产生受CD1d限制的脂质抗原，这些抗原激活iNKT细胞以产生Th1型和Th2型细胞因子。在此，我们表明SCD患者的循环iNKT细胞表达升高水平的外核苷三磷酸二磷酸水解酶CD39以及腺苷A2A受体（A2AR）。我们还研究了刺激培养的人iNKT细胞对参与嘌呤能信号调节的基因表达的影响。iNKT细胞刺激导致ADORA2A、P2RX7、CD38、CD39、ENPP1、CD73、PANX1和ENT1的诱导。降解腺苷的ADA的转录减少。CD39 mRNA的诱导与iNKT细胞上外ATP酶活性增加相关，该活性被POM1阻断。在刺激过程中iNKT细胞暴露于A2AR激动剂减少了干扰素 - γ的产生，并增强了白细胞介素 - 13和CD39的产生。基于这些发现，我们将“嘌呤能Th2型细胞因子偏向”定义为对iNKT细胞刺激的一种抗炎嘌呤能反应，这种反应是由参与嘌呤释放、细胞外代谢和信号传导的几个基因转录的变化引起的。