Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

Dakappagari, Naveen; Maruyama, Toshiaki; Renshaw, Mark W.; Tacken, Paul J.; Figdor, Carl G.; Torensma, Ruurd; Wild, Martha A.; Wu, Dayang; Bowdish, Katherine S.; Kretz-Rommel, Anke

doi:10.4049/jimmunol.176.1.426

Cited by 52 publications

(35 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression of DC-SIGN is particularly well suited to ATV approaches as the receptor is expressed at high levels by multiple DC populations that can contribute to T-cell priming and activation. Similar to MR, DC-SIGN is an endocytic receptor that can mediate efficient antigen presentation through different ligands, and more recently using a novel humanized antibody, hD1 (Schjetne et al, 2002;Tacken et al, 2005;Dakappagari et al, 2006).…”

Section: Dc-sign Dc-specific Icam-grabbing Non-integrin (Dc-sign)mentioning

confidence: 99%

Antibody-targeted vaccines

Keler

Ramakrishna

et al. 2007

Oncogene

View full text Add to dashboard Cite

Section: Dc-sign Dc-specific Icam-grabbing Non-integrin (Dc-sign)mentioning

confidence: 99%

Antibody-targeted vaccines

Keler

Ramakrishna

et al. 2007

Oncogene

View full text Add to dashboard Cite

“…Most particularly, targeting antigens through the DC surface lectins DCIR [18,78], DC-SIGN [79], Dectin [80], Clec9A [81], and Langerin [82], results in humoral and/or cellular CD4 + and/or CD8 + T-cell responses. In the absence of adjuvants, targeting DEC205 + DCs in vivo can induce tolerance [75].…”

Section: Vaccination Via Dcs: In Vivo DC Targetingmentioning

confidence: 99%

Human Dendritic Cell Subsets for Vaccination

Dubsky¹,

Ueno²,

Piqueras³

et al. 2005

J Clin Immunol

View full text Add to dashboard Cite

Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural targets for antigen delivery. DCs provide an essential link between the innate and the adaptive immune responses. DCs are at the center of the immune system owing to their ability to control both tolerance and immunity. DCs are thus key targets for both preventive and therapeutic vaccination. Herein, we will discuss recent progresses in our understanding of DC subsets physiology as it applies to vaccination.Dendritic cells (DCs) are key regulators of innate and adaptive immune responses [1,2]. The plasticity of DCs in response to extrinsic signals and the existence of distinct DC subsets with distinct functions contribute to the mounting of highly diverse immune responses. DCs are essential in pathogen resistance including different viruses, bacteria and parasites as demonstrated using DC-depleted mice [3]. Vaccine adjuvants primarily act via activation of DCs. Preventive vaccines are designed to initiate protective humoral immune responses. Today, more than 70 preventive vaccines have been licensed for use against approximately 30 microbes, sparing countless lives [4 •• ]. However, effective vaccines remain elusive for diseases such as human immunodeficiency virus (HIV)-induced acquired immune deficiency syndrome, plasmodium-induced malaria, virus-induced hepatitis C, and Mycobacterium-induced tuberculosis, to cite a few [4 •• ]. Most of these are chronic diseases for which it is thought that strong cellular immunity, in particular cytotoxic T cells, is necessary to eliminate the cells that are infected with the causative agent. Therapeutic vaccines have been designed to eliminate existing diseases and cancer represents an important target for such therapeutic vaccines. Early studies also indicate that vaccines might also be developed in noninfectious settings for the treatment of allergy, and autoimmunity. Here we will discuss recent insights and current views on the biology of human DC subsets in the context of vaccination. Human DC subsetsWhile there has been considerable progress in understanding the ontogeny of mouse DC subsets [5,6], less is known on the origin of human DCs and their differentiation program. This is due to their rarity in the blood, the poor accessibility of human tissues and the limited experimental approaches that can be applied to humans. Care should be taken, however, in extending the data generated from mouse DC subsets to human DC subsets. The knowledge of human DC subsets came from studies on blood and skin DC subsets. These studies have distinguished human-blood-circulating DC subsets based on three main cell surface markers: CD303 (BDCA-2) on plasmacytoid DCs (pDCs), CD1c (or BDCA-1) expressed on the majority of circulating DCs and CD141 (or BDCA-3) expressed on a minute population [7][8][9]. Human CD141 + CD1c − DCs uniquely express Toll like receptor 3; produce IL-12 and Corresponding authors: Palucka, Karolina (karolinp@baylorhealth.edu) and Bancherea...

show abstract

“…The observation that DC-SIGN is effectively internalized by singlechain antibodies suggests that internalization is not dependent on receptor cross-linking, as is essential when targeting Fc receptors. [11][12][13] We previously demonstrated that ligand binding to the CRD of DC-SIGN results in clathrin-mediated internalization of the receptor and routing to late endosomal, LAMP-1, and MHC class II positive, compartments. 8,9,14,15 The observation of SierraFilardi et al, showing that antibodies recognizing the neck domain of DC-SIGN display an enhanced ability to trigger receptor internalization compared with CRD-binding antibodies, 16 prompted us to initiate a detailed study on antigen uptake and processing when targeting different epitopes of DC-SIGN.…”

Section: Introductionmentioning

confidence: 99%

Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation

Tacken

Ginter

Berod

et al. 2011

Blood

110

View full text Add to dashboard Cite

Targeting antigens to dendritic cell (DC)-specific receptors, such as DC-SIGN, induces potent T cell-mediated immune responses. DC-SIGN is a transmembrane C-type lectin receptor with a long extracellular neck region and a carbohydrate recognition domain (CRD). Thus far, only antibodies binding the CRD have been used to target antigens to DC-SIGN. We evaluated the endocytic pathway triggered by antineck antibodies as well as their intracellular routing and ability to induce CD8 ؉ T-cell activation. In contrast to anti-CRD antibodies, antineck antibodies induced a clathrin-independent mode of DC-SIGN internalization, as demonstrated by the lack of colocalization with clathrin and the observation that silencing clathrin did not affect antibody internalization in human DCs. Interestingly, we observed that anti-neck and anti-CRD antibodies were differentially routed within DCs. Whereas anti-CRD antibodies were mainly routed to late endosomal compartments, anti-neck antibodies remained associated with early endosomal compartments positive for EEA-1 and MHC class I for up to 2 hours after internalization. Finally, cross-presentation of protein antigen conjugated to antineck antibodies was approximately 1000-fold more effective than nonconjugated antigen. Our studies demonstrate that anti-neck antibodies trigger a distinct mode of DC-SIGN internalization that shows potential for targeted vaccination strategies. IntroductionDendritic cells (DCs) play a key role in initiating adaptive immune responses by capturing antigens and presenting them to T cells. The discovery of receptors that are mainly expressed by DCs, such as several members of the C-type lectin receptor (CLR) family, allows for vaccination strategies that target antigens directly to DCs in vivo. 1 Targeted delivery of antigens through CLRs stimulates antigen presentation and results in immunity when DC maturation stimuli are coadministered. 2 Although most of the vaccines currently on the market mainly induce humoral responses, many DC-targeted vaccines also induce strong cytotoxic T cell (CTL) responses. 1 This is attributed to the ability of certain DC subsets to present exogenous antigens on MHC class I, a process called cross-presentation.CLRs bind carbohydrate structures in a Ca 2ϩ -dependent manner via their carbohydrate recognition domain (CRD). The CRD binds specific mannose, galactose, or fucose structures present on self or non-self-proteins. 3 Human DC-SIGN represents a member of the CLR family that has been explored for DC vaccination strategies. The extracellular part of DC-SIGN is composed of a C-terminal CRD and a neck region consisting of 7 complete, and 1 incomplete, 23-residue tandem repeat regions. DC-SIGN has been demonstrated to recognize many pathogens, including viruses, bacteria, fungi, and parasites. 4 After binding, these pathogens are internalized and pathogen-derived antigens are presented via MHC class I and II molecules to CD8 ϩ and CD4 ϩ T cells, respectively. 5,6 By analogy, vaccination strategies targeting antigens to the CR...

show abstract

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

Cited by 52 publications

References 48 publications

Antibody-targeted vaccines

Antibody-targeted vaccines

Human Dendritic Cell Subsets for Vaccination

Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation

Contact Info

Product

Resources

About