期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2004
卷号:101
期号:30
页码:11058-11063
DOI:10.1073/pnas.0307927101
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要: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 naive 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.