Trudeau Institute, 154 Algonquin Ave, Saranac Lake, NY 12983, USA.
Aging Cell. 2012 Oct;11(5):732-40. doi: 10.1111/j.1474-9726.2012.00836.x. Epub 2012 Jun 11.
CD4 T cells, and especially T follicular helper cells, are critical for the generation of a robust humoral response to an infection or vaccination. Importantly, immunosenescence affects CD4 T-cell function, and the accumulation of intrinsic defects decreases the cognate helper functions of these cells. However, much less is known about the contribution of the aged microenvironment to this impaired CD4 T-cell response. In this study, we have employed a preclinical model to determine whether the aged environment contributes to the defects in CD4 T-cell functions with aging. Using an adoptive transfer model in mice, we demonstrate for the first time that the aged microenvironment negatively impacts at least three steps of the CD4 T-cell response to antigenic stimulation. First, the recruitment of CD4 T cells to the spleen is reduced in aged compared to young hosts, which correlates with dysregulated chemokine expression in the aged organ. Second, the priming of CD4 T cells by DCs is reduced in aged compared to young mice. Finally, naïve CD4 T cells show a reduced transition to a T follicular helper cell phenotype in the aged environment, which impairs the subsequent generation of germinal centers. These studies have provided new insights into how aging impacts the immune system and how these changes influence the development of immunity to infections or vaccinations.
CD4 T 细胞，尤其是滤泡辅助性 T 细胞，对于针对感染或疫苗接种产生强大的体液免疫反应至关重要。重要的是，免疫衰老会影响 CD4 T 细胞的功能，内在缺陷的积累会降低这些细胞的同源辅助功能。然而，对于衰老微环境对这种受损的 CD4 T 细胞反应的贡献，人们知之甚少。在这项研究中，我们采用了临床前模型来确定衰老的环境是否会导致 CD4 T 细胞功能随着年龄的增长而出现缺陷。通过在小鼠中使用过继转移模型，我们首次证明衰老的微环境会对 CD4 T 细胞对抗原刺激的反应的至少三个步骤产生负面影响。首先，与年轻宿主相比，衰老宿主中 CD4 T 细胞向脾脏的募集减少，这与衰老器官中趋化因子表达失调有关。其次，与年轻小鼠相比，衰老小鼠中 DC 对 CD4 T 细胞的初始激活减少。最后，在衰老环境中，幼稚 CD4 T 细胞向滤泡辅助性 T 细胞表型的转化减少，这会损害生发中心的随后生成。这些研究为我们提供了新的见解，了解衰老如何影响免疫系统，以及这些变化如何影响对感染或疫苗接种的免疫反应的发展。
