Department of Laboratory Diagnostics, University Medical Centre Maribor, Maribor, Slovenia;
Medical Faculty, University of Maribor, Maribor, Slovenia.
J Leukoc Biol. 2017 Jun;101(6):1405-1418. doi: 10.1189/jlb.5A0416-194R. Epub 2017 Mar 2.
Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (T). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RAFOXP3 activated regulatory T cells (aT) were described. We assessed T/T subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty-one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4 T cell subsets but not in the aT subset, which was significantly decreased in patients with SLE. In contrast to aT, SLE T displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of T-expressing proliferation marker Ki-67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased T-pSTAT5/aT-pSTAT5 ratio experienced a more aggressive-relapsing disease course and displayed higher time-adjusted cumulative CD4 T cell pSTAT5 levels during follow-up, which were positively correlated with time-adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to T over aT and could represent a possible marker of SLE disease severity.
STAT5 信号通路的激活上调了抗凋亡蛋白 Bcl2，并驱动自身反应性常规 CD4 T 细胞（T 细胞）的增殖。在系统性红斑狼疮（SLE）中，描述了 T 细胞 Bcl2 含量增加和 CD45RAFOXP3 激活的调节性 T 细胞（aT）的平衡失调。我们通过常规流式细胞术和成像流式细胞术评估了 SLE 患者血液 T 细胞中的 T/T 亚群和 STAT5 的磷酸化（pSTAT5）。纳入了 41 例 SLE 患者、33 名健康对照者和 29 名类风湿关节炎患者。对 39 例 SLE 患者进行了长期监测，最长随访时间达 1000d。SLE 患者 T 细胞中 Bcl2 蛋白含量的显著增加与依赖 IL-7 的 STAT5 激活相关，表现为基础水平和核定位的 pSTAT5 增加。FOXP3 低表达的 CD4 T 细胞亚群中 pSTAT5 水平显著增加，但在 aT 亚群中未增加，而 SLE 患者的 aT 亚群显著减少。与 aT 不同，SLE T 显示出显著增加的 pSTAT5 和 Bcl2 水平。此外，SLE 患者的 T 细胞表达增殖标志物 Ki-67 的比例显著增加，且与 CD4 T 细胞 pSTAT5 水平呈正相关。最后，一个以 T-pSTAT5/aT-pSTAT5 比值增加为特征的患者亚组经历了更具侵袭性的复发性疾病过程，并且在随访期间显示出更高的时间调整累积 CD4 T 细胞 pSTAT5 水平，这与时间调整累积疾病活动呈正相关。我们的结果表明，不平衡的 STAT5 磷酸化与 Bcl2 和 Ki-67 的表达有关，可能赋予 T 细胞比 aT 细胞更强的生存和增殖优势，并且可能成为 SLE 疾病严重程度的一个潜在标志物。
