Research Center on Aging, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 1036 rue Belvedere sud, Sherbrooke, J1H 4C4, Quebec, Canada.
Cell Commun Signal. 2014 Jan 9;12:2. doi: 10.1186/1478-811X-12-2.
Immune responses are generally impaired in aged mammals. T cells have been extensively studied in this context due to the initial discovery of their reduced proliferative capacity with aging. The decreased responses involve altered signaling events associated with the early steps of T cell activation. The underlying causes of these changes are not fully understood but point to alterations in assembly of the machinery for T cell activation. Here, we have tested the hypothesis that the T cell pool in elderly subjects displayed reduced functional capacities due to altered negative feedback mechanisms that participate in the regulation of the early steps of T cell activation. Such conditions tip the immune balance in favor of altered T cell activation and a related decreased response in aging.
We present evidence that the tyrosine phosphatase SHP-1, a key regulator of T cell signal transduction machinery is, at least in part, responsible for the impaired T cell activation in aging. We used tyrosine-specific mAbs and Western blot analysis to show that a deregulation of the Csk/PAG loop in activated T cells from elderly individuals favored the inactive form of tyrosine-phosphorylated Lck (Y505). Confocal microscopy analysis revealed that the dynamic movements of these regulatory proteins in lipid raft microdomains was altered in T cells of aged individuals. Enzymic assays showed that SHP-1 activity was upregulated in T cells of aged donors, in contrast to young subjects. Pharmacological inhibition of SHP-1 resulted in recovery of TCR/CD28-dependent lymphocyte proliferation and IL-2 production of aged individuals to levels approaching those of young donors. Significant differences in the active (Y394) and inactive (Y505) phosphorylation sites of Lck in response to T cell activation were observed in elderly donors as compared to young subjects, independently of CD45 isoform expression.
Our data suggest that the role of SHP-1 in T cell activation extends to its increased effect in negative feedback in aging. Modulation of SHP-1 activity could be a target to restore altered T cell functions in aging. These observations could have far reaching consequences for improvement of immunosenescence and its clinical consequences such as infections, altered response to vaccination.
免疫反应在老年哺乳动物中通常受到损害。由于最初发现 T 细胞随着衰老而增殖能力降低，因此对 T 细胞进行了广泛的研究。这些反应的减少涉及与 T 细胞活化早期步骤相关的信号转导事件的改变。这些变化的根本原因尚不完全清楚，但表明 T 细胞活化机制的组装发生了改变。在这里，我们检验了以下假设：由于参与 T 细胞活化早期步骤调节的负反馈机制发生改变，老年受试者的 T 细胞池表现出降低的功能能力。这种情况使免疫平衡有利于改变的 T 细胞活化和相关的衰老时的反应降低。
我们提供的证据表明，酪氨酸磷酸酶 SHP-1 是 T 细胞信号转导机制的关键调节剂，至少部分原因是衰老导致 T 细胞活化受损。我们使用酪氨酸特异性 mAb 和 Western blot 分析表明，来自老年人的激活 T 细胞中 Csk/PAG 环的失调有利于 Lck（Y505）的非活性酪氨酸磷酸化形式。共焦显微镜分析显示，这些调节蛋白在脂质筏微域中的动态运动在老年人的 T 细胞中发生改变。酶测定表明，与年轻供体相比，老年供体的 T 细胞中 SHP-1 活性上调。SHP-1 的药理学抑制导致 TCR/CD28 依赖性淋巴细胞增殖和 IL-2 产生的恢复，接近年轻供体的水平。与年轻供体相比，在老年人中观察到 T 细胞活化时 Lck 的活性（Y394）和非活性（Y505）磷酸化位点的显著差异，而与 CD45 同工型表达无关。
我们的数据表明，SHP-1 在 T 细胞活化中的作用扩展到其在衰老时负反馈中的增强作用。SHP-1 活性的调节可能是恢复衰老时改变的 T 细胞功能的目标。这些观察结果可能对改善免疫衰老及其临床后果（如感染、疫苗接种反应改变）产生深远影响。
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