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通过白介素-7 耗竭和抗 CD3 刺激调节体外人 T 细胞发育。

Regulation of in vitro human T cell development through interleukin-7 deprivation and anti-CD3 stimulation.

机构信息

Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

出版信息

BMC Immunol. 2012 Aug 16;13:46. doi: 10.1186/1471-2172-13-46.

DOI:10.1186/1471-2172-13-46
PMID:22897934
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3496569/
Abstract

BACKGROUND

The role of IL-7 and pre-TCR signaling during T cell development has been well characterized in murine but not in human system. We and others have reported that human BM hematopoietic progenitor cells (HPCs) display poor proliferation, inefficient double negative (DN) to double positive (DP) transition and no functional maturation in the in vitro OP9-Delta-like 1 (DL1) culture system.

RESULTS

In this study, we investigated the importance of optimal IL-7 and pre-TCR signaling during adult human T cell development. Using a modified OP9-DL1 culture ectopically expressing IL-7 and Fms-like tyrosine kinase 3 ligand (Flt3L), we demonstrated enhanced T cell precursor expansion. IL-7 removal at various time points during T cell development promoted a slight increase of DP cells; however, these cells did not differentiate further and underwent cell death. As pre-TCR signaling rescues DN cells from programmed cell death, we treated the culture with anti-CD3 antibody. Upon pre-TCR stimulation, the IL-7 deprived T precursors differentiated into CD3+TCRαβ+DP cells and further matured into functional CD4 T cells, albeit displayed a skewed TCR Vβ repertoire.

CONCLUSIONS

Our study establishes for the first time a critical control for differentiation and maturation of adult human T cells from HPCs by concomitant regulation of IL-7 and pre-TCR signaling.

摘要

背景

IL-7 和 pre-TCR 信号在 T 细胞发育中的作用在鼠类中得到了很好的描述，但在人类系统中尚未得到描述。我们和其他人已经报道，人类 BM 造血祖细胞 (HPCs) 在体外 OP9-Delta-like 1 (DL1) 培养系统中显示出增殖能力差、低效的双阴性 (DN) 到双阳性 (DP) 过渡和无功能成熟。

结果

在这项研究中，我们研究了在成人人类 T 细胞发育过程中最佳 IL-7 和 pre-TCR 信号的重要性。使用过表达 IL-7 和 Fms 样酪氨酸激酶 3 配体 (Flt3L) 的改良 OP9-DL1 培养，我们证明了 T 细胞前体的扩增增强。在 T 细胞发育的各个时间点去除 IL-7 会略微增加 DP 细胞的数量；然而，这些细胞不会进一步分化并发生细胞死亡。由于 pre-TCR 信号可挽救 DN 细胞免于程序性细胞死亡，我们用抗 CD3 抗体处理培养物。在 pre-TCR 刺激后，IL-7 剥夺的 T 前体分化为 CD3+TCRαβ+DP 细胞，并进一步成熟为功能性 CD4 T 细胞，尽管表现出偏向性 TCR Vβ 库。

结论

我们的研究首次建立了通过同时调节 IL-7 和 pre-TCR 信号来控制成人人类 HPCs 中 T 细胞分化和成熟的关键控制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/b2a7c4b6f976/1471-2172-13-46-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/d150f1bfb5fa/1471-2172-13-46-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/04cf90ccc98e/1471-2172-13-46-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/60a32c47d367/1471-2172-13-46-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/0b80bb504198/1471-2172-13-46-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/074db7623898/1471-2172-13-46-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/7004618ceb25/1471-2172-13-46-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/d960674834ac/1471-2172-13-46-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/c69e6e2b227e/1471-2172-13-46-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/b2a7c4b6f976/1471-2172-13-46-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/d150f1bfb5fa/1471-2172-13-46-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/04cf90ccc98e/1471-2172-13-46-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/60a32c47d367/1471-2172-13-46-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/0b80bb504198/1471-2172-13-46-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/074db7623898/1471-2172-13-46-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/7004618ceb25/1471-2172-13-46-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/d960674834ac/1471-2172-13-46-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/c69e6e2b227e/1471-2172-13-46-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1479/3496569/b2a7c4b6f976/1471-2172-13-46-9.jpg

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