Article

Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication.

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Nature Immunology (Impact Factor: 24.97). 07/2007; 8(6):569-77. DOI: 10.1038/ni1470
Source: PubMed

ABSTRACT DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.

0 Followers
 · 
96 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Among myeloid immune receptors, C-type lectin receptors (CLRs) have a remarkable capacity to sense a variety of self and non-self ligands. The coupling of CLRs to different signal transduction modules is influenced not only by the receptor, but also by the nature, density and architecture of the ligand, which can affect the rate of receptor internalization and trafficking to diverse intracellular compartments. Understanding how the variety of self and non-self ligands triggers differential CLR signalling and function presents a fascinating biological challenge. Non-self ligands usually promote inflammation and immunity, whereas self ligands are frequently involved in communication and tolerance. But pathogens can mimic self-inhibitory signals to escape immune surveillance, and endogenous ligands can contribute to the sensing of pathogens through CLRs. In this review, we survey the complexity and flexibility in functional outcome found in the myeloid CLRs, which is not only based on their differing intracellular motifs, but is also conditioned by the physical nature, affinity and avidity of the ligand.
    Immunobiology 09/2014; 220(2). DOI:10.1016/j.imbio.2014.09.013 · 3.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Innate recognition of virus proteins is an important component of the immune response to viral pathogens. A component of this immune recognition is the family of lectins; pattern recognition receptors (PRRs) that recognise viral pathogen-associated molecular patterns (PAMPs) including viral glycoproteins. In this review we discuss the contribution of soluble and membrane-associated PRRs to immunity against virus pathogens, and the potential role of these molecules in facilitating virus replication. These processes are illustrated with examples of viruses including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Ebola virus (EBOV). We focus on the structure, function and genetics of the well-characterised C-type lectin mannose-binding lectin, the ficolins, and the membrane-bound CD209 proteins expressed on dendritic cells. The potential for lectin-based antiviral therapies is also discussed.
    Molecules 01/2015; 20(2):2229-2271. DOI:10.3390/molecules20022229 · 2.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Targeting antigens to dendritic cell (DC) surface receptors using antibodies has been successfully used to generate strong immune responses and is currently in clinical trials for cancer immunotherapy. Whilst cancer immunotherapy focuses on the induction of CD8(+) T-cell responses, many successful vaccines to pathogens or their toxins utilize humoral immunity as the primary effector mechanism. Universally, these approaches have used adjuvants or pathogen material that augment humoral responses. However, adjuvants are associated with safety issues. One approach, successfully used in the mouse, to generate strong humoral responses in the absence of adjuvant is to target antigen to Clec9A, also known as DNGR-1, a receptor on CD8α(+) DCs. Here, we address two issues relating to clinical application. First, we address the issue of variable adjuvant-dependence for different antibodies targeting mouse Clec9A. We show that multiple sites on Clec9A can be successfully targeted, but that strong in vivo binding and provision of suitable helper T cell determinants was essential for efficacy. Second, we show that induction of humoral immunity to CLEC9A-targeted antigens is extremely effective in non-human primates, in an adjuvant-free setting. Our findings support extending this vaccination approach to humans and offer important insights into targeting design. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 03/2015; 45(3). DOI:10.1002/eji.201445127 · 4.52 Impact Factor

Full-text (2 Sources)

Download
24 Downloads
Available from
Jun 10, 2014