title: The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility.
abstract: Integrity of the dendritic cell (DC) actin cytoskeleton is essential for T cell priming, but the underlying mechanisms are poorly understood. We show that the DC F-actin network regulates the lateral mobility of intracellular cell adhesion molecule 1 (ICAM-1), but not MHCII. ICAM-1 mobility and clustering are regulated by maturation-induced changes in the expression and activation of moesin and α-actinin-1, which associate with actin filaments and the ICAM-1 cytoplasmic domain. Constrained ICAM-1 mobility is important for DC function, as DCs expressing a high-mobility ICAM-1 mutant lacking the cytoplasmic domain exhibit diminished antigen-dependent conjugate formation and T cell priming. These defects are associated with inefficient induction of leukocyte functional antigen 1 (LFA-1) affinity maturation, which is consistent with a model in which constrained ICAM-1 mobility opposes forces on LFA-1 exerted by the T cell cytoskeleton, whereas ICAM-1 clustering enhances valency and further promotes ligand-dependent LFA-1 activation. Our results reveal an important new mechanism through which the DC cytoskeleton regulates receptor activation at the immunological synapse.
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19102.
authors: William A
authors: WA
authors: Comrie
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19102.
authors: Shuixing
authors: S
authors: Li
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19102.
authors: Sarah
authors: S
authors: Boyle
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19102 jburkhar@mail.med.upenn.edu.
authors: Janis K
authors: JK
authors: Burkhardt
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics; D005802:Genes, MHC Class II / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D016415:Sequence Alignment
chemical_list: C528567:Actn1 protein, mouse; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D000185:Actinin; D018799:Intercellular Adhesion Molecule-1; C071058:moesin