VLA-4 Integrin Concentrates at the Peripheral Supramolecular Activation Complex of the Immune Synapse and Drives T Helper 1 Responses

The integrin α4β1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides co-stimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of α4β1 during the formation of the immune synapse is currently unknown. Here, we...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-07, Vol.101 (30), p.11058-11063
Main Authors: Mittelbrunn, María, Molina, Ana, Escribese, María M., Yáñez-Mó, María, Escudero, Ester, Ursa, Ángeles, Tejedor, Reyes, Mampaso, Francisco, Sánchez-Madrid, Francisco, Steinman, Ralph M.
Format: Article
Language:English
Subjects:
Adhesion
Animals
Antibodies
Antigen-Presenting Cells - immunology
B lymphocytes
Biological Sciences
CD4-Positive T-Lymphocytes - immunology
Cell adhesion
Cell lines
Cells, Cultured
Coculture Techniques
Cytokines
Dendritic Cells - immunology
Epitopes
Flow Cytometry
Humans
Immune system
Immunology
Integrin alpha4beta1 - analysis
Integrin alpha4beta1 - immunology
Integrins
Jurkat Cells
Leukocytes
Ligands
Lymphocyte Activation
Microscopy, Fluorescence
Molecules
Rats
Rats, Inbred BN
T lymphocytes
Th1 Cells - immunology
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Summary:The integrin α4β1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides co-stimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of α4β1 during the formation of the immune synapse is currently unknown. Here, we show that α4β1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-α4 antibodies, VLA-4 colocalizes with the CD3-ζ chain at the center of the synapse. In addition, antibody engagement of α4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4+T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-α4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of α4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0307927101