van der Vlist M, de Witte L, de Vries RD et al.Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4(+) T cells but are incapable of cross-presentation. Eur J Immunol 41:2619-2631

Center of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
European Journal of Immunology (Impact Factor: 4.03). 07/2011; 41(9):2619-31. DOI: 10.1002/eji.201041305
Source: PubMed


Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4(+) T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8(+) T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to cross-present MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8(+) T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8(+) T-cell priming via the endogenous antigen presentation pathway.

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Available from: Rory D de Vries, Feb 12, 2014
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    • "Similar to DC-SIGN, langerin recognizes pathogens such as HIV, Candida, Saccharomyces and measles virus (MV) in a glycan-dependent manner [27] [28] [29]. Although the targeting of antigens to langerin using moabs lead to the development of antigen-specific Th1 and CD8 + T-cell responses[13], langerin-mediated internalization of MV only induced MV-specific CD4 + T cell responses, but no antigen cross-presentation occurred [28]. It is currently unclear A C C E P T E D M A N U S C R I P T "
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    ABSTRACT: Dendritic cells (DCs) and Langerhans cells (LC) are professional antigen presenting cells (APCs) that initiate humoral and cellular immune responses. Targeted delivery of antigen towards DC- or LC-specific receptors enhances vaccine efficacy. In this study, we compared the efficiency of glycan-based antigen targeting to both the human DC-specific C-type lectin receptor (CLR) DC-SIGN and the LC-specific CLR langerin. Since DC-SIGN and langerin are able to recognize the difucosylated oligosaccharide Lewis Y (Le(Y)), we prepared neoglycoconjugates bearing this glycan epitope to allow targeting of both lectins. Le(Y)-modified liposomes, with an approximate diameter of 200nm, were significantly endocytosed by DC-SIGN(+) DCs and mediated efficient antigen presentation to CD4(+) and CD8(+) T cells. Surprisingly, although langerin bound to Le(Y)-modified liposomes, LCs exposed to Le(Y)-modified liposomes could not endocytose liposomes nor mediate antigen presentation to T cells. However, LCs mediated an enhanced cross-presentation when antigen was delivered through langerin using Le(Y)-modified synthetic long peptides. In contrast, Le(Y)-modified synthetic long peptides were recognized by DC-SIGN, but did not trigger antigen internalization nor antigen cross-presentation. These data demonstrate that langerin and DC-SIGN have different size requirements for antigen uptake. Although using glycans remains an interesting option in the design of anti-cancer vaccines targeting multiple CLRs, aspects such as molecule size and conformation need to be taken in consideration. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 02/2015; 203. DOI:10.1016/j.jconrel.2015.01.040 · 7.71 Impact Factor
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    • "The ligands for DC-SIGN are both MV glycoproteins F and H in contrast to CD46, SLAM and PVRL4 where only H is required [37]. In addition, human primary Langerin cells (a subset of DCs) are capable of capturing MV through the C-type lectin Langerin [38]. Glycosaminoglycans (GAG) have been shown to have a role in infection by a tissue culture-adapted vaccine strain of RPV and recombinant wt strains of CDV as well as MV [15]; [39], [40]. "
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    ABSTRACT: Signalling lymphocyte activation molecule (SLAM) has been identified as an immune cell receptor for the morbilliviruses, measles (MV), canine distemper (CDV), rinderpest and peste des petits ruminants (PPRV) viruses, while CD46 is a receptor for vaccine strains of MV. More recently poliovirus like receptor 4 (PVRL4), also known as nectin 4, has been identified as a receptor for MV, CDV and PPRV on the basolateral surface of polarised epithelial cells. PVRL4 is also up-regulated by MV in human brain endothelial cells. Utilisation of PVRL4 as a receptor by phocine distemper virus (PDV) remains to be demonstrated as well as confirmation of use of SLAM. We have observed that unlike wild type (wt) MV or wtCDV, wtPDV strains replicate in African green monkey kidney Vero cells without prior adaptation, suggesting the use of a further receptor. We therefore examined candidate molecules, glycosaminoglycans (GAG) and the tetraspan proteins, integrin β and the membrane bound form of heparin binding epithelial growth factor (proHB-EGF),for receptor usage by wtPDV in Vero cells. We show that wtPDV replicates in Chinese hamster ovary (CHO) cells expressing SLAM and PVRL4. Similar wtPDV titres are produced in Vero and VeroSLAM cells but more limited fusion occurs in the latter. Infection of Vero cells was not inhibited by anti-CD46 antibody. Removal/disruption of GAG decreased fusion but not the titre of virus. Treatment with anti-integrin β antibody increased rather than decreased infection of Vero cells by wtPDV. However, infection was inhibited by antibody to HB-EGF and the virus replicated in CHO-proHB-EGF cells, indicating use of this molecule as a receptor. Common use of SLAM and PVRL4 by morbilliviruses increases the possibility of cross-species infection. Lack of a requirement for wtPDV adaptation to Vero cells raises the possibility of usage of proHB-EGF as a receptor in vivo but requires further investigation.
    PLoS ONE 08/2014; 9(8):e106281. DOI:10.1371/journal.pone.0106281 · 3.23 Impact Factor
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    • "A side-by-side comparison of in vitro-derived LCs with CD14+ DCs suggests the two DC subset have similar capacity for cross-presentation (36). Importantly, LCs isolated from skin are incapable of cross-presentation of captured antigen, while they can present antigen on MHCII to CD4+ T cells (36, 56). Whether this deficiency is the result of the isolation procedure or a true characteristic of LCs remains to be confirmed. "
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    ABSTRACT: Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8(+) T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs. This is done via selective targeting of antigen using monoclonal antibodies directed against endocytic receptors on the surface of the DCs. In this review, we will discuss considerations relevant to the design of such vaccines: the existence of DC subsets with specialized functions, the impact of the antigen intracellular trafficking on cross-presentation, and the influence of maturation signals received by DCs on the outcome of the immune response.
    Frontiers in Immunology 05/2014; 5:255. DOI:10.3389/fimmu.2014.00255
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