Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4300 West Markham St., Little Rock, AR 72205, USA.
Cell Mol Immunol. 2012 Jan;9(1):86-96. doi: 10.1038/cmi.2011.41. Epub 2011 Oct 10.
Physiological aging imposes significant alterations in the repertoire of T cells and all associated functions. Although several studies have reported defects upon antigen-induced activation of T cells during aging, the molecular mechanisms that control T-cell receptor (TCR) downmodulation remain to be fully defined. While previous studies have assessed the role of F-actin in regulating activation-induced TCR internalization, few have delineated the roles of motor proteins, such as non-muscle myosin IIA (NMMIIA). In this study, we describe a series of experiments supporting the hypothesis that effective TCR downmodulation requires not only efficient reorganization of the actin cytoskeleton, but also functional NMMIIA. For the first time, we show that CD4(+) T cells from elderly human donors have dysfunctional NMMIIA that contributes to delaying activation-induced TCR internalization and impairing calcium mobilization. Additionally, our results demonstrate that chemical inhibition of NMMIIA in CD4(+) T cells from young donors also results in complete abrogation of TCR internalization, strongly supporting the fundamental role of NMMIIA in modulating this event. Recent observations that the generation of an efficient T-cell response requires migration prompted us to investigate whether NMMIIA also plays a regulatory role in CD4(+) T-cell migration. We show that chemical inhibition of NMMIIA downmodulates chemotactic migration in CD4(+) T cells from both young and elderly donors. Together, these data demonstrate a significant contribution of dysfunctional NMMIIA to TCR-mediated functional defects during aging.
生理衰老对 T 细胞的 repertoire 和所有相关功能造成显著改变。尽管有几项研究报告称，T 细胞在衰老过程中抗原诱导激活时存在缺陷，但控制 T 细胞受体 (TCR) 下调的分子机制仍有待充分定义。虽然先前的研究评估了 F-肌动蛋白在调节激活诱导的 TCR 内化中的作用，但很少有研究阐明运动蛋白（如非肌肉肌球蛋白 IIA（NMMIIA））的作用。在这项研究中，我们描述了一系列实验，支持了以下假说：有效的 TCR 下调不仅需要有效的肌动蛋白细胞骨架重组，还需要功能性的 NMMIIA。我们首次表明，老年人类供体的 CD4(+) T 细胞存在功能失调的 NMMIIA，这导致激活诱导的 TCR 内化延迟，并损害钙动员。此外，我们的结果表明，在年轻供体的 CD4(+) T 细胞中化学抑制 NMMIIA 也会导致 TCR 内化完全阻断，这强烈支持 NMMIIA 在调节此事件中的基本作用。最近的观察表明，产生有效的 T 细胞反应需要迁移，这促使我们研究 NMMIIA 是否也在 CD4(+) T 细胞迁移中发挥调节作用。我们表明，化学抑制 NMMIIA 会下调年轻和老年供体的 CD4(+) T 细胞的趋化性迁移。总之，这些数据表明功能失调的 NMMIIA 对衰老过程中 TCR 介导的功能缺陷有重要贡献。
