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Influence of ₁ Integrin Intracytoplasmic Domains in the Regulation of VLA-4-Mediated Adhesion of Human T Cells to VCAM-1 under Flow Conditions¹

Maria Alessandra Rosenthal-Allieri^*,, Michel Ticchioni^*,, Jean Philippe Breittmayer^*, Yoji Shimizu and Alain Bernard^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 576, Nice, France; Laboratoire d’Immunologie, Centre Hospitalier Universitaire, Nice, France; and Department of Laboratory Medicine and Pathology, Center for Immunology and Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455

The VLA-4 integrin supports static cell-cell, cell-matrix adhesion, and dynamic interactions with VCAM-1. Although functions for well-conserved ₁ integrin cytoplasmic domains in regulating static cell adhesion has been established, the molecular basis for ₁ integrin-dependent arrest on VCAM-1 under flow conditions remains poorly understood. We have transfected the ₁ integrin-deficient A1 Jurkat T cell line with ₁ 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 ₁ 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 ₁ 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.

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