National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
J Leukoc Biol. 2010 Jan;87(1):43-9. doi: 10.1189/jlb.0209086. Epub 2009 Oct 1.
An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28(+) CD8 memory T cells over their CD28(-) counterparts, as CD28(+) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28(+) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28(+) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.
人类免疫反应随着年龄的增长而下降，其特征是 CD28(-) CD8 T 细胞的积累，这归因于重复的抗原刺激和细胞因子如 IL-15 介导的稳态增殖。然而，负责维持 CD28 表达的细胞因子的身份知之甚少。在这里，我们报告了 IL-21 在调节年轻和老年供体的 CD8 记忆 T 细胞中 IL-15 介导的生长和 CD28 表达中的作用。我们表明，IL-21 促使更多的 IL-15 刺激细胞进入细胞分裂并发生凋亡。此外，IL-21 优先增强 CD28(+) CD8 记忆 T 细胞对其 CD28(-) 对应物的 IL-15 诱导的增殖，因为 CD28(+) 细胞在受到 IL-15 和 IL-21 刺激时表达更高水平的 IL-15R 和 IL-21R 以及更大的 pSTAT5。此外，IL-21 降低了 IL-15 诱导的 CD8 记忆 T 细胞中 CD28 的下调。最后，CD28(+) CD8 记忆 T 细胞对稳态细胞因子 IL-15 和 IL-21 的增殖和存活能力随着年龄的增长而保持良好。总之，这些发现表明，IL-21 增强了 CD8 记忆 T 细胞，特别是 CD28(+)记忆 T 细胞对 IL-15 的增殖反应，并且还作为 IL-15 诱导的 CD28(-) CD8 T 细胞增加的拮抗剂。
