Dynamin2 controls Rap1 activation and integrin clustering in human T lymphocyte adhesion

Leukocyte trafficking is crucial to facilitate efficient immune responses. Here, we report that the large GTPase dynamin2, which is generally considered to have a key role in endocytosis and membrane remodeling, is an essential regulator of integrin-dependent human T lymphocyte adhesion and migration. Chemical inhibition or knockdown of dynamin2 expression significantly reduced integrin-dependent T cell adhesion in vitro. This phenotype was not observed when T cells were treated with various chemical inhibitors which abrogate endocytosis or actin polymerization. We furthermore detected dynamin2 in signaling complexes and propose that it controls T cell adhesion via FAK/Pyk2- and RapGEF1-mediated Rap1 activation. In addition, the dynamin2 inhibitor-induced reduction of lymphocyte adhesion can be rescued by Rap1a overexpression. We demonstrate that the dynamin2 effect on T cell adhesion does not involve integrin affinity regulation but instead relies on its ability to modulate integrin valency. Taken together, we suggest a previously unidentified role of dynamin2 in the regulation of integrin-mediated lymphocyte adhesion via a Rap1 signaling pathway.

白细胞迁移（Leukocyte trafficking）对于介导高效的免疫应答至关重要。本研究证实，通常被认为在胞吞作用与膜重塑中发挥关键作用的大型GTP酶动力蛋白2（dynamin2），是整合素依赖的人T淋巴细胞黏附与迁移的必需调控因子。体外实验中，对动力蛋白2进行化学抑制或基因敲低，可显著降低整合素依赖的T细胞黏附水平；而采用多种可阻断胞吞作用或肌动蛋白聚合的化学抑制剂处理T细胞时，并未观察到该表型。研究团队进一步在信号复合物中检测到动力蛋白2，并提出其可通过FAK/Pyk2与Rap鸟苷酸交换因子1（RapGEF1）介导的Rap1激活通路调控T细胞黏附。此外，过表达Rap1a可挽救动力蛋白2抑制剂诱导的淋巴细胞黏附水平下降。本研究证实，动力蛋白2对T细胞黏附的调控并不涉及整合素亲和力调控，而是依赖于其调节整合素价态的能力。综上，本研究揭示了动力蛋白2此前未被报道的功能：通过Rap1信号通路调控整合素介导的淋巴细胞黏附。