Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation-known to inhibit Th17 differentiation in mouse models-was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling.

中文翻译：

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PD-L1的上调抑制了STAT3功能丧失和STAT1功能获得者的Th17细胞分化。

STAT3中亚型突变的患者和STAT1中亚型突变的患者具有几种临床和细胞表型，提示其病理生理机制重叠。因此，我们在这些队列中研究了细胞因子信号传导和CD4 + T细胞分化，以表征常见途径。如预期的那样，在两个队列中均破坏了Th17细胞的分化。我们发现在这两个队列中，STAT1均响应细胞因子刺激而被过度磷酸化，并且已知STAT1依赖的PD-L1上调（已知在小鼠模型中抑制Th17分化）也显着增强。SOCS3的过表达强烈抑制STAT1的磷酸化和PD-L1的上调，这表明SOCS3表达的减少可能导致所观察到的作用。Th17分化的缺陷可以通过PD-L1抑制在体外得以克服，在STAT3功能丧失的小鼠模型中，可以通过将它们与PD-1敲除小鼠杂交来克服。PD-L1可能是影响细胞因子信号传导的几种免疫缺陷遗传病的潜在治疗靶标。