Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration.
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.
Department of Biomedical Research, National Jewish Health, Denver, CO 80206.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Miriam L
ML
Estin
Department of Biomedical Research, National Jewish Health, Denver, CO 80206.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Scott B
SB
Thompson
Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Brianna
B
Traxinger
Department of Biomedical Research, National Jewish Health, Denver, CO 80206.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Marlie H
MH
Fisher
Department of Biomedical Research, National Jewish Health, Denver, CO 80206.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Rachel S
RS
Friedman
Department of Biomedical Research, National Jewish Health, Denver, CO 80206; jacobellij@njhealth.org.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Jordan
J
Jacobelli
D000199:Actins / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D007249:Inflammation / Q000473:pathology; D039441:Integrin alpha4 / Q000378:metabolism; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D000098662:Vasodilator-Stimulated Phosphoprotein
D000199:Actins; D015815:Cell Adhesion Molecules; C102177:Evl protein, mouse; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D039441:Integrin alpha4
T cell; cytoskeleton; extravasation; migration