Hernández-López Carmen, Varas Alberto, Sacedón Rosa, Jiménez Eva, Muñoz Juan José, Zapata Agustín G, Vicente Angeles
Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.
Blood. 2002 Jan 15;99(2):546-54. doi: 10.1182/blood.v99.2.546.
The present study investigated the potential role of stromal cell-derived factor 1 (SDF-1) in human intrathymic T-cell differentiation. Results show that SDF-1 is produced by human thymic epithelial cells from the subcapsular and medullary areas, and its receptor, CXCR4, is up-regulated on CD34(+) precursor cells committed to the T-cell lineage. Chimeric human-mouse fetal thymus organ culture (FTOC) seeded with purified CD34(+) thymic progenitors and treated with neutralizing antibodies against SDF-1 or CXCR4 showed a significant reduction of the number of human thymocytes and an arrested thymocyte differentiation in the transition between CD34(+) precursor cells and CD4(+) immature thymocytes. SDF-1-treated FTOC showed an increase of human thymocyte numbers, mainly affecting the most immature subpopulations. Moreover, these results suggest that CXCR4/SDF-1 signaling is not critical for the CD34(+) cell precursor recruitment to the thymus. On the other hand, SDF-1 significantly increased the viability of CD34(+) T-cell precursors modulating the expression of BCL-2 and BAX genes, and stimulated the proliferation of CD34(+) thymic precursor cells, particularly in synergy with interleukin 7 (IL-7), but not with other cytokines, such as stem cell factor or flt3-ligand. Accordingly, only IL-7 was able to up-regulate CXCR4 expression on CD34(+) thymic progenitors. In addition, deprivation of SDF-1 partially inhibited human thymocyte expansion induced by IL-7 in human-mouse FTOC. This study indicates that SDF-1/CXCR4 signaling is required for the survival, expansion, and subsequent differentiation of human early thymocytes and identifies a new mechanism by which IL-7 mediates its effects on human thymopoiesis.
本研究调查了基质细胞衍生因子1（SDF-1）在人胸腺内T细胞分化中的潜在作用。结果显示，SDF-1由人胸腺被膜下和髓质区域的胸腺上皮细胞产生，其受体CXCR4在定向于T细胞谱系的CD34(+)前体细胞上上调。用纯化的CD34(+)胸腺祖细胞接种并经抗SDF-1或CXCR4中和抗体处理的人-小鼠嵌合胎儿胸腺器官培养（FTOC）显示，人胸腺细胞数量显著减少，且在CD34(+)前体细胞与CD4(+)未成熟胸腺细胞之间的过渡阶段胸腺细胞分化停滞。经SDF-1处理的FTOC显示人胸腺细胞数量增加，主要影响最不成熟的亚群。此外，这些结果表明CXCR4/SDF-1信号对于CD34(+)细胞前体募集到胸腺并不关键。另一方面，SDF-1通过调节BCL-2和BAX基因的表达显著提高了CD34(+) T细胞前体的活力，并刺激了CD34(+)胸腺前体细胞的增殖，特别是与白细胞介素7（IL-7）协同作用时，但与其他细胞因子，如干细胞因子或flt3配体协同作用时则不然。因此，只有IL-7能够上调CD34(+)胸腺祖细胞上CXCR4的表达。此外，去除SDF-1部分抑制了人-小鼠FTOC中IL-7诱导的人胸腺细胞扩增。本研究表明，SDF-1/CXCR4信号对于人早期胸腺细胞的存活、扩增及随后的分化是必需的，并确定了IL-7介导其对人胸腺生成作用的一种新机制。
