title: VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses.
abstract: The integrin alpha 4 beta 1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of alpha 4 beta 1 during the formation of the immune synapse is currently unknown. Here, we show that alpha 4 beta 1 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-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse. In addition, antibody engagement of alpha 4 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-alpha 4 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 alpha 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.
authors.affiliation: Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Mittelbrunn
authors.forename: Ana
authors.initials: A
authors.lastname: Molina
authors.forename: María M
authors.initials: MM
authors.lastname: Escribese
authors.forename: María
authors.initials: M
authors.lastname: Yáñez-Mó
authors.forename: Ester
authors.initials: E
authors.lastname: Escudero
authors.forename: Angeles
authors.initials: A
authors.lastname: Ursa
authors.forename: Reyes
authors.initials: R
authors.lastname: Tejedor
authors.forename: Francisco
authors.initials: F
authors.lastname: Mampaso
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D039041:Integrin alpha4beta1 / Q000032:analysis / Q000276:immunology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008856:Microscopy, Fluorescence; D051381:Rats; D011914:Rats, Inbred BN; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D039041:Integrin alpha4beta1