Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
Blood. 2010 Mar 11;115(10):1897-905. doi: 10.1182/blood-2009-08-237784. Epub 2009 Dec 1.
T lymphopoiesis requires settling of the thymus by bone marrow-derived precursors throughout adult life. Progenitor entry into the thymus is selective, but the molecular basis of this selectivity is incompletely understood. The chemokine receptor CCR9 has been demonstrated to be important in this process. However, progenitors lacking CCR9 can still enter the thymus, suggesting a role for additional molecules. Here we report that the chemokine receptor CCR7 is also required for efficient thymic settling. CCR7 is selectively expressed on bone marrow progenitors previously shown to have the capacity to settle the thymus, and CCR7(-/-) progenitors are defective in settling the thymus. We further demonstrate that CCR7 sustains thymic settling in the absence of CCR9. Mice deficient for both CCR7 and CCR9 have severe reductions in the number of early thymic progenitors, and in competitive assays CCR7(-/-)CCR9(-/-) double knockout progenitors are almost completely restricted from thymic settling. However, these mice possess near-normal thymic cellularity. Compensatory expansion of intrathymic populations can account for at least a part of this recovery. Together our results illustrate the critical role of chemokine receptor signaling in thymic settling and help to clarify the cellular identity of the physiologic thymic settling progenitors.
T 细胞发育需要骨髓来源的前体在整个成年期定居于胸腺。前体进入胸腺是有选择性的，但这种选择性的分子基础尚未完全理解。趋化因子受体 CCR9 已被证明在这个过程中很重要。然而，缺乏 CCR9 的祖细胞仍然可以进入胸腺，这表明还需要其他分子的参与。在这里，我们报告趋化因子受体 CCR7 也需要有效地进入胸腺定居。CCR7 选择性地表现在以前被证明有能力定居于胸腺的骨髓祖细胞上，而 CCR7(-/-)祖细胞在定居于胸腺方面存在缺陷。我们进一步证明 CCR7 在缺乏 CCR9 的情况下维持胸腺定居。同时缺乏 CCR7 和 CCR9 的小鼠，早期胸腺祖细胞的数量严重减少，在竞争实验中，CCR7(-/-)CCR9(-/-)双敲除祖细胞几乎完全被排除于胸腺定居之外。然而，这些小鼠具有接近正常的胸腺细胞数量。胸腺内群体的代偿性扩增至少可以解释部分恢复现象。我们的结果共同说明了趋化因子受体信号在胸腺定居中的关键作用，并有助于阐明生理性胸腺定居祖细胞的细胞特性。
