Thymic B cell development is controlled by the B potential of progenitors via both hematopoietic-intrinsic and thymic microenvironment-intrinsic regulatory mechanisms.
Thymic B cell development is controlled by the B potential of progenitors via both hematopoietic-intrinsic and thymic microenvironment-intrinsic regulatory mechanisms.
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DOI：
10.1371/journal.pone.0193189
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Manley NR
中科院分区：
文献类型：
--
作者：
Xiao S;Zhang W;Manley NR
从出生到成年的造血干细胞 (HSC) 对胸腺中的 T 或 B 细胞命运具有不同的分化潜力；与成人 HSC 相比，新生儿骨髓 (BM) 细胞在 BM 中产生 B 细胞的潜力也更高。我们假设这种造血内在 B 潜能也可能在个体发育过程中调节胸腺中 B 细胞的发育。 Foxn1lacZ 突变小鼠是一种模型，其中胸腺上皮细胞 (TEC) 特异性转录因子在出生后一周开始下调，导致胸腺细胞产量急剧减少。在这项研究中，我们发现这些突变体在围产期虽然 T 细胞减少，但胸腺 B 细胞的频率大大增加。我们使用该模型来表征胸腺控制 B 细胞发育的机制。 Foxn1lacZ 突变体中，T 细胞定型胸腺内祖细胞 (DN1a,b) 从出生后 1 周开始逐渐减少，而胸腺 B 细胞在 3-4 周时达到峰值，具有前 B-II 祖细胞表型，并且起源于胸腺。异时性嵌合体表明，胸腺 B 细胞产生的能力是由于新生儿 HSC 较高的 B 潜力与胸腺微环境缺陷（包括 DL4 的减少和促进 B 细胞命运的 IL-7 的增加）相结合。我们的研究结果表明，胸腺 B 细胞产生的能力和时间过程主要受个体发育期间 B 细胞本身的造血内在潜力控制，但来自 TEC 微环境的信号也会影响胸腺中 B 细胞发育的频率和分化潜力。
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.