Sun Liguang, Brown Robert, Chen Shande, Zhuge Qichuan, Su Dong-Ming
Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.
Aging (Albany NY). 2012 Sep;4(9):606-19. doi: 10.18632/aging.100487.
Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells. Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew. By grafting young wild-type (WT) BM progenitors into aged IL-7R-/- hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation. Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.
与年龄相关的T细胞生成能力下降与两个主要淋巴器官——骨髓（BM）和胸腺有关。这两个器官都含有淋巴造血祖细胞/干细胞（LPCs）和非造血基质/微环境细胞。小鼠模型显示，这种下降并非由于LPCs数量减少，也不是LPCs自身的缺陷，而是其微环境细胞的缺陷。然而，老年BM祖细胞存在髓系偏向这一事实对这一观点提出了挑战。通过将年轻的野生型（WT）BM祖细胞移植到老年IL-7R-/-宿主中，尽管LPCs有缺陷，但这些宿主拥有与WT相当的微环境，我们证明这些年轻的BM祖细胞也表现出髓系偏向。此外，我们还证明，在体内微环境中，移植的胎儿胸腺招募的老年BM祖细胞能够与其年轻的对应细胞竞争，尽管在传统的BM移植中，体外处理的老年BM细胞无法做到这一点。随着机体年龄的增长，LPCs及其微环境细胞都不可避免地会衰老，但通过对胸腺T淋巴细胞生成的观察发现，微环境细胞的衰老比LPCs早得多。因此，衰老导致的T细胞生成能力下降主要取决于BM和胸腺中祖细胞微环境细胞的状态。
