Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Neurosciences, College of Medicine, University of South Florida, 3515 E. Fletcher Ave. Tampa, FL 33613, USA.
FASEB J. 2012 Mar;26(3):1040-51. doi: 10.1096/fj.11-195438. Epub 2011 Nov 15.
Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.
在自闭症患者中观察到 T 淋巴细胞群体和功能异常。可溶性淀粉样前体蛋白 α（sAPP-α）在一些自闭症患者中升高，已知其由免疫细胞产生。鉴于 sAPP-α 在神经元增殖、生长和存活中的既定作用，我们假设其在免疫系统中具有类似的作用。因此，我们探讨了 sAPP-α 是否可以调节免疫发育和功能，特别是免疫系统适应性臂的尖峰细胞：T 细胞。为此，我们生成了过表达人 sAPP-α 的小鼠，并对 T 细胞发育、信号转导、细胞因子产生和先天/适应性免疫功能的各个方面进行了特征描述。在这里，我们报告称，过表达转基因 sAPP-α（TgsAPP-α）的小鼠显示出 CD8（+）T 细胞比例增加，而效应记忆 T 细胞在胸腺中减少。总体而言，胸腺中的凋亡信号转导降低，这与 Notch1 激活的急剧升高相关；而活性 caspase-3/总 caspase-3 和 Bax/Bcl-2 比值降低。用 T 细胞有丝分裂原体外刺激 TgsAPP-α 小鼠脾细胞后，观察到 IFN-γ、IL-2 和 IL-4 的水平升高。最后，在免疫接种后，TgsAPP-α 小鼠的脾细胞在回忆抗原刺激后显示出 IFN-γ、IL-2 和 IL-4 水平降低，以及 ZAP70 激活受到抑制。鉴于一些自闭症患者中循环 sAPP-α 水平升高，sAPP-α 可能会导致这些患者中观察到的某些免疫功能障碍，包括 T 细胞凋亡失调、PI3K/AKT 信号转导异常、细胞因子改变和 T 细胞回忆刺激受损。
