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.

患者在减效突变STAT3和患者的hypermorphic突变STAT1分享一些临床和细胞表型暗示重叠的病理生理机制。因此，我们检查了细胞因子信号传导和CD4 ⁺这些队列中的T细胞分化是常见途径的特征。如预期的那样，在两个队列中均破坏了Th17细胞的分化。我们发现这两个队列中的STAT1都响应细胞因子刺激而被过度磷酸化，并且STAT1依赖性PD-L1上调（已知在小鼠模型中抑制Th17分化）也得到了显着增强。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。