Abstract
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.
Highlights
T lymphocytes are crucial for proper adaptive immune responses
T cells are suitable for studying leukocyte adhesion as they do not adhere to mere plastic and depend on adhesion-inducing stimuli in order to stick to specific integrin ligands (S1A and S1B Fig)
Our work shows that dynamin2 is a critical component of integrin valency regulation in CD4+ T cells and provides a detailed analysis of its role in adhesion regulation of human lymphocytes
Summary
T lymphocytes are crucial for proper adaptive immune responses Their function in homeostasis and inflammation strongly depends on their ability to adapt their adhesive state. Rapid switches of this state are achieved by regulating the main adhesion receptors of lymphocytes, the integrins [1]. T lymphocytes are able to control integrin activity fast and precisely in response to their given environment and specific stimuli, a process termed “inside-out” integrin activation [3]. This may be achieved by conformational changes in integrin molecules. Extracellular integrin domains undergo transitions from bent low affinity to extended high affinity conformations, triggered by separation
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