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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 ?-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.

SUBMITTER: Comrie WA

PROVIDER: S-EPMC4332244 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility.

Comrie William A WA Li Shuixing S Boyle Sarah S Burkhardt Janis K JK

The Journal of cell biology 20150209 4

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- ...[more]

PMID: 25666808

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Project description:The inadequate function of the antigen presenting cells, such as dendritic cells (DCs) in cancer is one of the major factors leading to compromised anti-tumor immune response. Cell-to-cell interactions and cell migration are essential features of the immunological response in cancer. Vascular endothelial growth factor (VEGF) has been shown to affect DCs differentiation and maturation processes, thus leading to impaired DCs function. This study aimed to compare the expression of adherence and cytoskeleton-related genes between mature monocyte-derived dendritic cells (mDCs) and mDCs previously exposed to VEGF (mDCVs). VEGF is known to stimulate cell migration and actin rearrangement, but its association with adhesion molecules has not been largely explored in the context of DCs. Our results show that immature human DCs exposed to VEGF up-regulated CD80 and CD86, typical cell surface markers of DC maturation. However, unlike mDCs, mDCVs showed alterations in cell morphology, with broad changes in the characteristic cytoplasmic processes. DNA microarray analysis revealed that mDCVs up-regulated a significant subset of genes related to cell migration, including cell adhesion molecules and related signaling pathways as well as cytoskeleton-related genes. Our results suggest that VEGF, known to be involved in the inhibition of DC maturation, interferes in cell mechanisms leading to cytoskeleton reorganization and the expression of cell adhesion molecules. Cell morphology is associated with DC maturation and migration, both impaired in pathological conditions such as cancer. Keywords: Gene expression profiling Gene expression profiling was carried out in freshly isolated CD14+ cells prior to cultivation (“D0” samples) and in DCs after 6 days (“D6” samples) and 7 days in culture, with or without VEGF treatment (“D7V” and “D7” samples, respectively). Blood samples were collected on the same day and processed concomitantly. Cell culture, RNA extraction, and microarray hybridization were also carried out simultaneously in an attempt to minimize technical inconsistencies. A total of 14 independent microarray hybridizations were carried out with oligonucleotide microarrays, covering approximately 55,000 human transcripts (Whole Genome CodeLink™ Bioarrays, GE Healthcare). Target preparation and hybridization procedures strictly followed protocols provided by the manufacturer.Arrays were scanned following the recommended scanning procedure and settings for use with CodeLink bioarrays (GE Healthcare) on GenePix 4000B Array Scanner/GenePix Pro 4.1 software (Axon Instruments).

Project description:Cell division, the purpose of which is to enable cell replication, and in particular to distribute complete, accurate copies of genetic material to daughter cells, is essential for the propagation of life. At a morphological level, division not only necessitates duplication of cellular structures, but it also relies on polar segregation of this material followed by physical scission of the parent cell. For these fundamental changes in cell shape and positioning to be achieved, mechanisms are required to link the cell cycle to the modulation of cytoarchitecture. Outside of mitosis, the three main cytoskeletal networks not only endow cells with a physical cytoplasmic skeleton, but they also provide a mechanism for spatio-temporal sensing via integrin-associated adhesion complexes and site-directed delivery of cargoes. During mitosis, some interphase functions are retained, but the architecture of the cytoskeleton changes dramatically, and there is a need to generate a mitotic spindle for chromosome segregation. An economical solution is to re-use existing cytoskeletal molecules: transcellular actin stress fibres remodel to create a rigid cortex and a cytokinetic furrow, while unipolar radial microtubules become the primary components of the bipolar spindle. This remodelling implies the existence of specific mechanisms that link the cell-cycle machinery to the control of adhesion and the cytoskeleton. In this article, we review the intimate three-way connection between microenvironmental sensing, adhesion signalling and cell proliferation, particularly in the contexts of normal growth control and aberrant tumour progression. As the morphological changes that occur during mitosis are ancient, the mechanisms linking the cell cycle to the cytoskeleton/adhesion signalling network are likely to be primordial in nature and we discuss recent advances that have elucidated elements of this link. A particular focus is the connection between CDK1 and cell adhesion. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.

Dataset Information

The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility.

Publications

The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility.

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