Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):379-84. doi: 10.1073/pnas.1314209111. Epub 2013 Dec 16.
Plexins and semaphorins comprise a large family of receptor-ligand pairs controlling cell guidance in nervous, immune, and vascular systems. How plexin regulation of neurite outgrowth, lymphoid trafficking, and vascular endothelial cell branching is linked to integrin function, central to most directed movement, remains unclear. Here we show that on developing thymocytes, plexinD1 controls surface topology of nanometer-scaled β1 integrin adhesion domains in cis, whereas its ligation by sema3E in trans regulates individual β1 integrin catch bonds. Loss of plexinD1 expression reduces β1 integrin clustering, thereby diminishing avidity, whereas sema3E ligation shortens individual integrin bond lifetimes under force to reduce stability. Consequently, both decreased expression of plexinD1 during developmental progression and a thymic medulla-emanating sema3E gradient enhance thymocyte movement toward the medulla, thus enforcing the orchestrated lymphoid trafficking required for effective immune repertoire selection. Our results demonstrate plexin-tunable molecular features of integrin adhesion with broad implications for many cellular processes.
衔接蛋白和神经递质素构成了一个庞大的受体-配体家族，它们控制着神经系统、免疫系统和脉管系统中的细胞导向。然而，衔接蛋白如何调节轴突生长、淋巴细胞迁移和血管内皮细胞分支，以及与整合素功能的关系，对于大多数定向运动至关重要，目前仍不清楚。在这里，我们发现，在发育中的胸腺细胞上，衔接蛋白 D1 能够在顺式调控纳米级 β1 整合素黏附域的表面拓扑结构，而其在反式被神经递质素 3E 结合则调控单个 β1 整合素捕获键。缺失衔接蛋白 D1 的表达会减少 β1 整合素的聚集，从而降低亲合力，而神经递质素 3E 的结合会缩短单个整合素键在力作用下的寿命，从而降低稳定性。因此，发育过程中衔接蛋白 D1 表达的降低和胸腺髓质发出的神经递质素 3E 梯度都会增强胸腺细胞向髓质的运动，从而强制进行协调的淋巴细胞迁移，以实现有效的免疫库选择。我们的研究结果表明，整合素黏附的衔接蛋白可调节分子特征，这对许多细胞过程具有广泛的影响。
