Cicin-Sain Luka, Messaoudi Ilhem, Park Byung, Currier Noreen, Planer Shannon, Fischer Miranda, Tackitt Shane, Nikolich-Zugich Dragana, Legasse Alfred, Axthelm Michael K, Picker Louis J, Mori Motomi, Nikolich-Zugich Janko
Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19960-5. doi: 10.1073/pnas.0705905104. Epub 2007 Dec 4.
The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G(1)-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.
初始T细胞的丢失是免疫衰老的一个标志。尽管胸腺退化是初始T细胞丢失的主要驱动因素,但对于其他机制在衰老灵长类动物初始T细胞耗竭中的作用了解较少。我们研究了恒河猴(RM)衰老过程中不同T细胞亚群的稳态循环和增殖性扩增的作用。在老年而非年轻成年RM的外周初始CD4 T细胞中,BrdU掺入和G(1)-M标志物Ki-67的表达升高,在初始CD8 T细胞中更为明显。增殖的初始细胞在老年动物中并未积累。相反,初始CD8 T细胞区室的相对大小与其增殖率呈负相关。同样,在初始CD8 T细胞增殖升高的个体中,T细胞受体多样性降低。这种明显的矛盾可以通过与初始库丢失相伴的周转率显著增加来解释。当初始CD8 T细胞库降至总血CD8细胞的4%以下时,周转率呈指数级增加。这些结果将初始T细胞库的缩小与稳态周转率的显著增加联系起来,这有可能加剧初始库的渐进性耗竭并限制T细胞库。因此,稳态T细胞增殖表现出时间上的拮抗性多效性,在成年期对T细胞维持有益,但对衰老个体的长期T细胞维持有害。
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