Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.A ctivated T-cell trafficking across the vascular endothelium is essential for ongoing immune surveillance of tissues and for effective immune responses to conditions such as infection and cancer. Conversely, in situations of immune dysregulation, inhibition of self-reactive T-cell trafficking represents a promising target for therapeutic immunomodulation. Disruption of these pathways, such as by antibody blockade of α4 integrins, is a highly effective approach to immunomodulation (1, 2). However, the molecular mechanisms by which chemokine receptor and adhesion molecule signaling induce the T-cell cytoskeletal machinery to promote extravasation are not yet fully elucidated.Transendothelial migration (TEM), the process by which T cells extravasate from the blood into tissues, is characterized by four distinct steps: rolling along the vascular wall, arrest or adhesion, intravascular crawling, and diapedesis across the endothelial barrier (3). Surface adhesion molecules play well-characterized roles in each step of the process. For example, the initial rolling step of TEM is facilitated by interactions between T-cell and endothelial selectins, whereas the adhesion, intravascular crawling, and diapedesis steps of TEM are mainly regulated by chemokineand shear force-stimulated modulation of lymphocyte functionassociated antigen 1 (LFA-1, αLβ2 integrin, CD11a/CD18) and very late antigen 4 (VLA-4, α4β1 integrin, CD49d/CD29) interactions with intracellular adhesion molecule 1 ...

SummaryThe field of megakaryocyte and platelet biology has been transformed with the implementation of high throughput sequencing. The use of modern sequencing technologies has led to the discovery of causative mutations in congenital platelet disorders and has been a useful tool in uncovering many other mechanisms of altered platelet formation and function. Although the understanding of the presence of RNA in platelets is relatively novel, mRNA and miRNA expression profiles are being shown to play an increasingly important role in megakaryopoiesis and platelet function in normal physiology as well as in disease states. Understanding the genetic perturbations underlying platelet dysfunction provides insight into normal megakaryopoiesis and thrombopoiesis, as well as guiding the development of novel therapeutics.

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