Antigen-experienced immune cells migrate back to the bone marrow (BM), where they are maintained in BM survival niches for an extended period. The composition of T cell subpopulations in the BM changes with age, leading to an accumulation of highly differentiated T cells and a loss of naïve T cells. While innate immune cells are also affected by age, little is known about interactions between different adaptive immune cell populations maintained in the BM. In this study, the phenotype and function of innate and adaptive immune cells isolated from human BM and peripheral blood (PB) was analysed in detail using flow cytometry, to determine if the accumulation of highly differentiated T and B cells, supported by the BM niches, limits the maintenance of other immune cells, or affects their functions such as providing protective antibody concentrations. Total T cells increase in the BM with age, as do highly differentiated CD8+ T cells which no longer express the co-stimulatory molecule CD28, while natural killer T (NKT) cells, monocytes, B cells, and naïve CD8+ T cells all decrease in the BM with age. A negative correlation of total T cells with B cells was observed in the BM. The percentage of B cells in the BM negatively correlated with highly differentiated CD8+CD28− T cells, replicative-senescent CD8+CD57+ T cells, as well as the CD8+CD28−CD57+ population. Similar correlations were seen between B cells and the frequency of highly differentiated T cells producing pro-inflammatory molecules in the BM. Interestingly, plasma concentrations of diphtheria-specific antibodies negatively correlated with highly differentiated CD8+CD57+ T cells as well as with exhausted central memory CD8+ and CD4+ T cells in the BM. A negative impact on diphtheria-specific antibodies was also observed for CD8+ T cells expressing senescence associated genes such as the cell cycle regulator p21 (CDKN1A), KLRG-1, and elevated levels of reactive oxygen species (ROS). Our data suggest that the accumulation and maintenance of highly differentiated, senescent, and exhausted T cells in the BM, particularly in old age, may interfere with the survival of other cell populations resident in the BM such as monocytes and B cells, leading to reduced peripheral diphtheria antibody concentrations as a result. These findings further highlight the importance of the BM in the long-term maintenance of immunological memory.

中文翻译：

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外周抗体浓度与人骨髓中高度分化的 T 细胞和炎症过程有关

经历过抗原的免疫细胞迁移回骨髓 (BM)，在那里它们在 BM 生存壁龛中维持较长时间。BM 中 T 细胞亚群的组成随着年龄的增长而变化，导致高度分化的 T 细胞的积累和幼稚 T 细胞的丧失。虽然先天免疫细胞也受到年龄的影响，但对维持在 BM 中的不同适应性免疫细胞群之间的相互作用知之甚少。在这项研究中，使用流式细胞术详细分析了从人 BM 和外周血 (PB) 中分离的先天性和适应性免疫细胞的表型和功能，以确定高度分化的 T 和 B 细胞的积累是否得到 BM 生态位的支持。 ，限制其他免疫细胞的维持，或影响它们的功能，例如提供保护性抗体浓度。随着年龄的增长，BM 中的总 T 细胞增加，不再表达共刺激分子 CD28 的高度分化的 CD8+ T 细胞也会增加，而自然杀伤 T (NKT) 细胞、单核细胞、B 细胞和幼稚 CD8+ T 细胞在BM 随年龄增长。在BM中观察到总T细胞与B细胞呈负相关。BM 中 B 细胞的百分比与高度分化的 CD8+CD28-T 细胞、复制性衰老 CD8+CD57+ T 细胞以及 CD8+CD28-CD57+ 群体呈负相关。在 B 细胞与在 BM 中产生促炎分子的高度分化 T 细胞的频率之间观察到类似的相关性。有趣的是，白喉特异性抗体的血浆浓度与高度分化的 CD8+CD57+ T 细胞以及 BM 中耗尽的中央记忆 CD8+ 和 CD4+ T 细胞呈负相关。对于表达衰老相关基因如细胞周期调节因子 p21 (CDKN1A)、KLRG-1 和活性氧 (ROS) 水平升高的 CD8+ T 细胞，也观察到对白喉特异性抗体的负面影响。我们的数据表明，BM 中高度分化、衰老和衰竭的 T 细胞的积累和维持，特别是在老年时，可能会干扰 BM 中其他细胞群（如单核细胞和 B 细胞）的存活，导致减少外周白喉抗体浓度。