Dendritic cells (DCs) devoid of the actin regulator Wiskott-Aldrich syndrome protein (WASp) show reduced directed migration and decreased formation of podosome adhesion structures. We examined DCs expressing a gain-of-function mutation in WASp, WASp L272P, identified in X-linked neutropenia patients. Analysis of WASp L272P DCs was compared to WASp-deficient DCs to examine how WASp activity influences DC migratory responses. In confined space, WASp-deficient DCs had increased migration speed whereas WASp L272P DCs had similar average speed but increased speed fluctuations, reduced displacement, and atypical rounded morphology, compared to wild-type (WT) DCs. Using an ear inflammation model and flow cytometry analysis, WT, WASp-deficient, and WASp L272P DCs were found to migrate in comparable numbers to the draining lymph nodes (LNs). However, histology analysis revealed that migratory DCs of WASp deficient and WASp L272P mice were mainly located in the collagenous capsule of the LN whereas WT DCs were located inside the LN. Analysis of ultrastructural features revealed that WASp L272P DCs had reduced cell area but formed larger podosome structures when compared to WT DCs. Together, our data suggest that WASp activity regulates DC migration and that loss-of-function and gain-of-function in WASp activity lead to different and phenotype-specific DC migratory behavior.

中文翻译：

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黄蜂 L272P 功能获得突变改变了肌动蛋白动力学的树突细胞协调，以促进迁移和粘附

缺乏肌动蛋白调节剂 Wiskott-Aldrich 综合征蛋白 (WASp) 的树突状细胞 (DC) 显示定向迁移减少和足体粘附结构的形成减少。我们检查了在 X 连锁中性粒细胞减少症患者中发现的 WASp、WASp L272P 中表达功能获得性突变的 DC。将 WASp L272P DC 的分析与 WASp 缺陷的 DC 进行比较，以检查 WASp 活动如何影响 DC 迁移反应。在密闭空间中，与野生型 (WT) DCs 相比，WASp 缺陷型 DCs 的迁移速度增加，而 WASp L272P DCs 的平均速度相似，但速度波动增加、位移减少和非典型圆形形态。使用耳部炎症模型和流式细胞术分析，发现 WT、WASp 缺陷和 WASp L272P DCs 迁移到引流淋巴结 (LNs) 的数量相当。然而，组织学分析显示 WASp 缺陷和 WASp L272P 小鼠的迁移 DCs 主要位于 LN 的胶原囊中，而 WT DCs 位于 LN 内。对超微结构特征的分析表明，与 WT DCs 相比，WASp L272P DCs 的细胞面积减少，但形成了更大的足体结构。总之，我们的数据表明 WASp 活动调节 DC 迁移，并且 WASp 活动中的功能丧失和功能获得导致不同的和表型特异性的 DC 迁移行为。对超微结构特征的分析表明，与 WT DCs 相比，WASp L272P DCs 的细胞面积减少，但形成了更大的足体结构。总之，我们的数据表明 WASp 活动调节 DC 迁移，并且 WASp 活动中的功能丧失和功能获得导致不同的和表型特异性的 DC 迁移行为。对超微结构特征的分析表明，与 WT DCs 相比，WASp L272P DCs 的细胞面积减少，但形成了更大的足体结构。总之，我们的数据表明 WASp 活动调节 DC 迁移，并且 WASp 活动中的功能丧失和功能获得导致不同的和表型特异性的 DC 迁移行为。