Influence of β1 integrin intracytoplasmic domains in the regulation of VLA-4-mediated adhesion of human T cells to VCAM-1 under flow conditions

Maria Alessandra Rosenthal-Allieri, Michel Ticchioni, Jean Philippe Breittmayer, Yoji Shimizu, Alain Bernard

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The VLA-4 integrin supports static cell-cell, cell-matrix adhesion, and dynamic interactions with VCAM-1. Although functions for well-conserved β1 integrin cytoplasmic domains in regulating static cell adhesion has been established, the molecular basis for β1 integrin-dependent arrest on VCAM-1 under flow conditions remains poorly understood. We have transfected the β1 integrin-deficient A1 Jurkat T cell line with β1 cDNA constructs with deletions of the NPXY motifs and specific mutations of tyrosine residues. Deletion of either NPXY motif impaired static adhesion induced by CD2 or CD47 triggering or direct β1 integrin stimulation. In contrast, PMA-induced adhesion to VCAM-1 was unaffected by deletion of the NPIY motif and only slightly impaired by deletion of NPKY. Moreover, deletion of the NPIY motif resulted in enhanced rolling and reduced arrest on VCAM-1 under shear flow conditions. In contrast, deletion of the NPKY motif did not alter arrest under flow. Although tyrosine to phenylalanine substitutions within two NPXY motifs did not alter static adhesion to VCAM-1, these mutations enhanced arrest on VCAM-1 under flow conditions. Furthermore, although deletion of the C′-terminal 5 AA of the β1 cytoplasmic domain dramatically impaired activation-dependent static adhesion, it did not impair arrest on VCAM-1 under flow conditions. Thus, our results demonstrate distinct structural requirements for VLA-4 function under static and shear flow conditions. This may be relevant for VLA-4 activity regulation in different anatomic compartments, such as when circulating cells arrest on inflamed endothelium under shear flow and when resident cells in bone marrow interact with VCAM-1-positive stromal cells.

Original languageEnglish (US)
Pages (from-to)1214-1223
Number of pages10
JournalJournal of Immunology
Volume175
Issue number2
DOIs
StatePublished - Jul 15 2005

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