BACKGROUND Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK. The aim of this study was to assess whether ESRD affects TCR-mediated signaling and explore possibilities for intervening in ESRD-associated defective T-cell mediated immunity. RESULTS An age-associated decline in TCR-induced pERK-levels was observed in the different CD4+ (P < 0.05), but not CD8+, T-cell subsets from healthy individuals (HI). Interestingly, pERK-levels of CD4+ T-cell subsets from young ESRD patients were in between young and elderly HI. A differentiation-associated decline in TCR-induced ERK and p38 phosphorylation was observed in T cells, although TCR-induced p38 phosphorylation was not significantly affected by age and/or ESRD. Frequencies of TCR-induced CD69-expressing CD4+ T cells declined with age and were positively associated with pERK. In addition, an age-associated tendency of increased expression of DUSP6 was observed in CD4+ T cells of HI and DUSP6 expression in young ESRD patients was similar to old HI. Inhibition of DUSP6 significantly increased TCR-induced pERK-levels of CD4+ T cells in young and elderly ESRD patients, and elderly HI. CONCLUSIONS TCR-mediated phosphorylation of ERK is affected in young ESRD patients consistent with the concept of premature immunological T cell ageing. Inhibition of DUSP6 specific for pERK might be a potential intervention enhancing T-cell mediated immunity in ESRD patients.

中文翻译：

---

终末期肾脏疾病患者中pERK依赖性缺陷TCR介导的CD4 + T细胞活化。

背景技术患有终末期肾病（ESRD）的患者的T细胞系统过早衰弱了免疫反应。包括细胞外信号调节激酶（ERK）和p38在内的丝裂原活化蛋白激酶（MAPK），通过将细胞外信号转移到细胞内反应中来调节多种细胞程序。T细胞受体（TCR）诱导的ERK磷酸化（pERK）可能显示与年龄相关的下降，这可以通过抑制双重特异性磷酸酶（DUSP）6来逆转，该酶具有底物特异性，可对pERK进行去磷酸化。这项研究的目的是评估ESRD是否会影响TCR介导的信号传导，并探讨干预ESRD相关缺陷T细胞介导的免疫的可能性。结果在健康个体（HI）的不同CD4 +（T <0.05）中，未观察到TCR诱导的pERK水平与年龄相关的下降（P <0.05）。有趣的是，年轻ESRD患者的CD4 + T细胞亚群的pERK水平介于年轻和老年HI之间。在T细胞中观察到了TCR诱导的ERK和p38磷酸化的分化相关下降，尽管TCR诱导的p38磷酸化不受年龄和/或ESRD的显着影响。TCR诱导的表达CD69的CD4 + T细胞的频率随年龄下降，并与pERK正相关。另外，在HI的CD4 + T细胞中观察到了与年龄相关的DUSP6表达增加的趋势，并且在年轻的ESRD患者中DUSP6的表达与老年HI相似。抑制DUSP6可以显着提高年轻和老年ESRD患者以及老年HI患者TCR诱导的CD4 + T细胞的pERK水平。结论TCR介导的ERK磷酸化在年轻ESRD患者中受到影响，这与免疫T细胞过早老化的概念一致。抑制pERK特异的DUSP6可能是增强ESRD患者T细胞介导免疫力的潜在干预措施。