Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 14, Pages E2901-E2910Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701886114
Keywords
T cell; migration; cytoskeleton; extravasation
Categories
Funding
- National Institute of Allergy and Infectious Diseases/NIH [R01AI125553, R56AI105111]
- Dana Foundation (Brain-Immuno Imaging grant)
- National Multiple Sclerosis Society (Pilot grant)
- American Society of Hematology
- NIH [T32AI007405]
- NIH/National Center for Advancing Translational Sciences Colorado CTSI TL1 [8TL1TR00155]
- NIH da [T32AI007405]
- Shared Instrumentation Grant [S10RR029218]
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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 naive T-cell trafficking to lymph nodes and spleen. Using amodel 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 alpha 4 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 alpha 4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a alpha 4 integrin-dependent manner.
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