Montero-Herradón Sara, García-Ceca Javier, Sánchez Del Collado Beatriz, Alfaro David, Zapata Agustín G
Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, C/José Antonio Novais 2, 28040, Madrid, Spain.
Histochem Cell Biol. 2016 Aug;146(2):167-82. doi: 10.1007/s00418-016-1431-x. Epub 2016 Apr 9.
Thymus development is a complex process in which cell-to-cell interactions between thymocytes and thymic epithelial cells (TECs) are essential to allow a proper maturation of both thymic cell components. Although signals that control thymocyte development are well known, mechanisms governing TEC maturation are poorly understood, especially those that regulate the maturation of immature TEC populations during early fetal thymus development. In this study, we show that EphB2-deficient, EphB2LacZ and EphB3-deficient fetal thymuses present a lower number of cells and delayed maturation of DN cell subsets compared to WT values. Moreover, deficits in the production of chemokines, known to be involved in the lymphoid seeding into the thymus, contribute in decreased proportions of intrathymic T cell progenitors (PIRA/B(+)) in the mutant thymuses from early stages of development. These features correlate with increased proportions of MTS20(+) cells but fewer MTS20(-) cells from E13.5 onward in the deficient thymuses, suggesting a delayed development of the first epithelial cells. In addition, in vitro the lack of thymocytes or the blockade of Eph/ephrin-B-mediated cell-to-cell interactions between either thymocytes-TECs or TECs-TECs in E13.5 fetal thymic lobes coursed with increased proportions of MTS20(+) TECs. This confirms, for the first time, that the presence of CD45(+) cells, corresponding at these stages to DN1 and DN2 cells, and Eph/ephrin-B-mediated heterotypic or homotypic cell interactions between thymocytes and TECs, or between TECs and themselves, contribute to the early maturation of MTS20(+) TECs.
胸腺发育是一个复杂的过程，其中胸腺细胞与胸腺上皮细胞（TECs）之间的细胞间相互作用对于使两种胸腺细胞成分都能正常成熟至关重要。尽管控制胸腺细胞发育的信号已为人熟知，但调控TEC成熟的机制却知之甚少，尤其是那些在胎儿胸腺发育早期调节未成熟TEC群体成熟的机制。在本研究中，我们发现与野生型（WT）相比，EphB2基因敲除、EphB2LacZ和EphB3基因敲除的胎儿胸腺细胞数量减少，DN细胞亚群成熟延迟。此外，已知参与淋巴细胞植入胸腺的趋化因子产生缺陷，导致突变胸腺中胸腺内T细胞祖细胞（PIRA/B(+)）的比例从发育早期就开始下降。这些特征与缺陷胸腺中从E13.5开始MTS20(+)细胞比例增加但MTS20(-)细胞减少相关，提示第一批上皮细胞发育延迟。此外，在体外，缺乏胸腺细胞或阻断E13.5胎儿胸腺叶中胸腺细胞-TECs或TECs-TECs之间Eph/ephrin-B介导的细胞间相互作用，会导致MTS20(+)TECs比例增加。这首次证实，在这些阶段对应于DN1和DN2细胞的CD45(+)细胞的存在，以及胸腺细胞与TECs之间或TECs与自身之间Eph/ephrin-B介导的异型或同型细胞相互作用，有助于MTS20(+)TECs的早期成熟。
