Department of Genetics, Paul D. Coverdell Center, University of Georgia, Athens, Georgia, United States of America.
PLoS One. 2018 Feb 20;13(2):e0193189. doi: 10.1371/journal.pone.0193189. eCollection 2018.
Hematopoietic stem cells (HSCs) derived from birth through adult possess differing differentiation potential for T or B cell fate in the thymus; neonatal bone marrow (BM) cells also have a higher potential for B cell production in BM compared to adult HSCs. We hypothesized that this hematopoietic-intrinsic B potential might also regulate B cell development in the thymus during ontogeny.
Foxn1lacZ mutant mice are a model in which down regulation of a thymic epithelial cell (TEC) specific transcription factor beginning one week postnatal causes a dramatic reduction of thymocytes production. In this study, we found that while T cells were decreased, the frequency of thymic B cells was greatly increased in these mutants in the perinatal period. We used this model to characterize the mechanisms in the thymus controlling B cell development.
Foxn1lacZ mutants, T cell committed intrathymic progenitors (DN1a,b) were progressively reduced beginning one week after birth, while thymic B cells peaked at 3-4 weeks with pre-B-II progenitor phenotype, and originated in the thymus. Heterochronic chimeras showed that the capacity for thymic B cell production was due to a combination of higher B potential of neonatal HSCs, combined with a thymic microenvironment deficiency including reduction of DL4 and increase of IL-7 that promoted B cell fate.
Our findings indicate that the capacity and time course for thymic B-cell production are primarily controlled by the hematopoietic-intrinsic potential for B cells themselves during ontogeny, but that signals from TECs microenvironment also influence the frequency and differentiation potential of B cell development in the thymus.
从出生到成年，造血干细胞（HSCs）在胸腺中具有不同的 T 细胞或 B 细胞命运分化潜能；与成年 HSCs 相比，新生儿骨髓（BM）细胞在 BM 中也具有更高的 B 细胞产生潜能。我们假设这种造血内在的 B 潜能也可能调节个体发生过程中胸腺中的 B 细胞发育。
Foxn1lacZ 突变小鼠是一种模型，其中从出生后一周开始，胸腺上皮细胞（TEC）特异性转录因子的下调导致胸腺细胞产生的急剧减少。在这项研究中，我们发现，虽然 T 细胞减少，但在这些突变体中，围产期的胸腺 B 细胞频率大大增加。我们利用这种模型来描述控制胸腺中 B 细胞发育的机制。
Foxn1lacZ 突变体中，T 细胞定向的胸腺内祖细胞（DN1a，b）从出生后一周开始逐渐减少，而胸腺 B 细胞在 3-4 周时达到高峰，具有前 B-II 祖细胞表型，起源于胸腺。异时嵌合体显示，胸腺 B 细胞产生的能力是由于新生儿 HSCs 的 B 潜能更高，加上 TEC 微环境缺陷的综合作用，包括 DL4 的减少和促进 B 细胞命运的 IL-7 的增加。
我们的研究结果表明，胸腺 B 细胞产生的能力和时间进程主要由个体发生过程中造血内在的 B 细胞潜能控制，但 TEC 微环境的信号也影响胸腺中 B 细胞发育的频率和分化潜能。
