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PI3Kδ promotes CD4(+) T-cell interactions with antigen-presenting cells by increasing LFA-1 binding to ICAM-1.

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Garçon, Fabien 


Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice.



Actin Depolymerizing Factors, Animals, Antigen-Presenting Cells, CD4-Positive T-Lymphocytes, Cell Adhesion, Cell Communication, Cell Movement, Cell Shape, Class I Phosphatidylinositol 3-Kinases, Dendritic Cells, GTP-Binding Proteins, Intercellular Adhesion Molecule-1, Lymph Nodes, Lymphocyte Function-Associated Antigen-1, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases, Protein Binding, Proto-Oncogene Proteins c-akt, Receptors, Antigen, T-Cell

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Immunol Cell Biol

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