The integrin ␣4␤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 ␣4␤1 during the formation of the immune synapse is currently unknown. Here, we show that ␣4␤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-␣4 antibodies, VLA-4 colocalizes with the CD3-chain at the center of the synapse. In addition, antibody engagement of ␣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-␣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 ␣4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.A fter the recognition of antigens (Ag) presented by dendritic cells (DCs), naïve T lymphocytes proliferate and differentiate into T helper (Th) 1 or 2 effector cells. These effector lymphocytes are characterized by distinct patterns of cytokine production and homing behavior. Th1 cells mainly produce IFN-␥ and IL-2 and have a key role in the cellular immune responses. Conversely, Th2 cells produce IL-4, IL-5, IL-6, and IL-10 and promote the humoral immune responses (1). DCs are the only Ag-presenting cells (APCs) involved in the priming of naïve Th cells and their polarization toward Th1 or Th2 differentiation. To acquire this capacity, DCs must undergo a maturation process characterized by the loss of their Ag-capturing capacity and the increase of their expression of costimulatory and adhesion molecules, including ␣4␤1 integrin (2). However, other APCs (e.g., B lymphocytes) are also involved in regulating the cytokine profiles of Th cell responses, indicating the importance of postpriming events (3).The interaction between T cells and APCs plays an important role in directing Th cell polarization. The strength of antigenic stimulation, the duration of T cell receptor engagement, the presence of different cytokines, and the participation of distinct costimulatory molecules are critical in determining the phenotype of differentiated T cells. The cytokine IL-12, high doses of Ag, and CD28͞B7-1 interaction promote Th1 differentiation, whereas an environment enriched in IL-4, low doses of Ag, and CD28͞B7-2 or inducible costimulator (ICOS)͞ICOS ligand participation promote Th2 responses (4).Integrins are a large family of ␣␤ heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix adhesion. Several integrins, lymphocyte functionassociated (LFA-1; ␣ L ␤ 2 ), very late activation antigen-4 (VLA-4; ␣4␤1), and VLA-1 (␣1␤1) have ...

tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.

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