Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.
Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, Toulouse, France.
Front Immunol. 2019 Dec 18;10:2970. doi: 10.3389/fimmu.2019.02970. eCollection 2019.
The CXCL12-CXCR4 axis plays a key role in the retention of stem cells and progenitors in dedicated bone marrow niches. It is well-known that CXCR4 responsiveness in B lymphocytes decreases dramatically during the final stages of their development in the bone marrow. However, the molecular mechanism underlying this regulation and whether it plays a role in B-cell homeostasis remain unknown. In the present study, we show that the differentiation of pre-B cells into immature and mature B cells is accompanied by modifications to the relative expression of chemokine receptors, with a two-fold downregulation of CXCR4 and upregulation of CCR7. We demonstrate that expression of CCR7 in B cells is involved in the selective inactivation of CXCR4, and that mature B cells from CCR7 mice display higher responsiveness to CXCL12 and improved retention in the bone marrow. We also provide molecular evidence supporting a model in which upregulation of CCR7 favors the formation of CXCR4-CCR7 heteromers, wherein CXCR4 is selectively impaired in its ability to activate certain G-protein complexes. Collectively, our results demonstrate that CCR7 behaves as a novel selective endogenous allosteric modulator of CXCR4.
CXCL12-CXCR4 轴在干细胞和祖细胞在特定骨髓龛中的保留中起着关键作用。众所周知，B 淋巴细胞在骨髓中的最后发育阶段，其对 CXCR4 的反应性会急剧下降。然而，这种调节的分子机制以及它是否在 B 细胞稳态中发挥作用仍不清楚。在本研究中，我们表明，前 B 细胞向未成熟和成熟 B 细胞的分化伴随着趋化因子受体的相对表达的改变，CXCR4 下调两倍，CCR7 上调。我们证明了 B 细胞中 CCR7 的表达参与了 CXCR4 的选择性失活，并且 CCR7 小鼠的成熟 B 细胞对 CXCL12 的反应性更高，在骨髓中的保留能力也得到了改善。我们还提供了支持以下模型的分子证据：CCR7 的上调有利于 CXCR4-CCR7 异二聚体的形成，其中 CXCR4 的某些 G 蛋白复合物的激活能力被选择性地削弱。总的来说，我们的研究结果表明 CCR7 作为 CXCR4 的新型选择性内源性变构调节剂发挥作用。
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