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Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated ?4?1 Integrins on T Cells.

ABSTRACT: Chemokine stimulation of integrin ?4?1-dependent T lymphocyte adhesion is a key step during lymphocyte trafficking. A central question regarding ?4?1 function is how its lateral mobility and organization influence its affinity and avidity following cell stimulation with chemokines and/or ligands. Using single particle tracking and superresolution imaging approaches, we explored the lateral mobility and spatial arrangement of individual ?4?1integrins on T cells exposed to different activating stimuli. We show that CXCL12 stimulation leads to rapid and transient ?4?1activation, measured by induction of the activation epitope recognized by the HUTS-21 anti-?1antibody and by increased talin-?1 association. CXCL12-dependent ?4?1 activation directly correlated with restricted lateral diffusion and integrin immobilization. Moreover, co-stimulation by CXCL12 together with soluble VCAM-1 potentiated integrin immobilization with a 5-fold increase in immobile integrins compared with unstimulated conditions. Our data indicate that docking by talin of the chemokine-activated ?4?1 to the actin cytoskeleton favors integrin immobilization, which likely facilitates ligand interaction and increased adhesiveness. Superresolution imaging showed that the nanoscale organization of high-affinity ?4?1 remains unaffected following chemokine and/or ligand addition. Instead, newly activated ?4?1 integrins organize on the cell membrane as independent units without joining pre-established integrin sites to contribute to cluster formation. Altogether, our results provide a rationale to understand how the spatiotemporal organization of activated ?4?1 integrins regulates T lymphocyte adhesion.

SUBMITTER: Sosa-Costa A

PROVIDER: S-EPMC5076515 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated α4β1 Integrins on T Cells.

Sosa-Costa Alberto A Isern de Val Sol S Sevilla-Movilla Silvia S Borgman Kyra J E KJ Manzo Carlo C Teixidó Joaquin J Garcia-Parajo Maria F MF

The Journal of biological chemistry 20160801 40

Chemokine stimulation of integrin α4β1-dependent T lymphocyte adhesion is a key step during lymphocyte trafficking. A central question regarding α4β1 function is how its lateral mobility and organization influence its affinity and avidity following cell stimulation with chemokines and/or ligands. Using single particle tracking and superresolution imaging approaches, we explored the lateral mobility and spatial arrangement of individual α4β1integrins on T cells exposed to different activating sti ...[more]

PMID: 27481944

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Project description:Diabetes reduces the number and induces dysfunction in circulating endothelial progenitor cells (EPCs) by mechanisms that are still uncovered. This study aims to evaluate the number, viability, phenotype, and function of EPCs in dyslipidemic mice with early diabetes mellitus and EPC infiltration in the aortic valve in order to identify possible therapeutic targets in diabetes-associated cardiovascular disease. A streptozotocin-induced diabetic apolipoprotein E knock-out (ApoE-/-) mouse model was used to identify the early and progressive changes, at 4 or 7 days on atherogenic diet after the last streptozotocin or citrate buffer injection. Blood and aortic valves from diabetic or nondiabetic ApoE-/- animals were collected.EPCs were identified as CD34 and vascular endothelial growth factor receptor 2 positive monocytes, and the expression levels of α4β1, αVβ3, αVβ5, β1, αLβ2, α5 integrins, and C-X-C chemokine receptor type 4 chemokine receptor on EPC surface were assessed by flow cytometry. The number of CD34 positive cells in the aortic valve, previously found to be recruited progenitor cells, was measured by fluorescence microscopy. Our results show that aortic valves from mice fed 7 days with atherogenic diet presented a significantly higher number of CD34 positive cells compared with mice fed only 4 days with the same diet, and diabetes reversed this finding. We also show a reduction of circulatory EPC numbers in diabetic mice caused by cell senescence and lower mobilization. Dyslipidemia induced EPC death through apoptosis regardless of the presence of diabetes, as shown by the higher percent of propidium iodide positive cells and higher cleaved caspase-3 levels. EPCs from diabetic mice expressed α4β1 and αVβ3 integrins at a lower level, while the rest of the integrins tested were unaffected by diabetes or diet. In conclusion, reduced EPC number and expression of α4β1 and αVβ3 integrins on EPCs at 4 and 7 days after diabetes induction in atherosclerosis-prone mice have resulted in lower recruitment of EPCs in the aortic valve.

Dataset Information

Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated ?4?1 Integrins on T Cells.

Publications

Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated α4β1 Integrins on T Cells.

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