In vivo targeting of human DC‐SIGN drastically enhances CD8⁺T‐cell‐mediated protective immunity

Abstract

Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8 + T-cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC-SIGN (DC-specific-ICAM3-grabbing-nonintegrin/CD209) is a C-type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC-SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC-SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti-DC-SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti-DC-SIGN antibodies conjugated to OVA induced strong and persistent antigen-specific CD4 + and CD8 + T-cell responses, which efficiently protected from infection with OVA-expressing Listeria monocytogenes. Thus, we propose DC targeting via DC-SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens. Keywords: Crosspresentation · DC-SIGN · Dendritic cells · Listeria · VaccineAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe development of effective vaccines against intracellular infectious agents is one of the biggest challenges in science and an urgent unmet medical need. In addition, other highly prevalent diseases like cancer strongly require new vaccination strategies Correspondence: Prof. Tim Sparwasser e-mail: tim.sparwasser@twincore.de that promote effective and long lasting cytotoxic CD8 + T-cell (CTL) responses.With the discovery of DCs in 1973 by the Nobel Prize laureate Ralph Steinman, a new window of opportunities opened in vaccine development. Consequently, for many years efforts have been made to develop vaccines based on ex vivo generated DCs * These authors equally contributed to this work. Eur. J. Immunol. 2013Immunol. . 43: 2543Immunol. -2553 carrying specific antigens from tumors or pathogens [1]. Although these studies showed promising results in mice and in a number of clinical studies, the production of antigen-bearing cellular DC vaccines is a labor intensive and costly procedure [1]. Therefore, it hardly represents an option to vaccinate against infectious diseases like tuberculosis, malaria, or HIV, which mainly affect developing countries. More recently, a new strategy has been explored to target defined antigens to DCs by using antibodies or glycosylated molecules that bind specific surface receptors directly in vivo [2][3][4]. Many of the receptors studied for DC targeting purposes belong to the family of C-type lec...

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

“…21 Importantly, delivery of antigens via anti-DC-SIGN monoclonal antibodies (aDC-SIGN) enhances T cell responses in vitro and in vivo. 18,19,22,23 An advantage of targeting antigens to CLRs is the possibility to modify antigens with the natural ligands of CLR, i.e., carbohydrates, which are small compared to antibodies. Glycans are naturally expressed throughout the body and therefore poorly immunogenic.…”

“…[25][26][27][28][29] In addition, we showed that in combination with an adjuvant, DC-SIGN triggering modulates cytokine responses 26 and elicits strong CD4 C and CD8 C effector T cell responses in murine and human models. 23,26 However, whether targeting antigens to CLRs such as DC-SIGN using glycans yields superior tumor immunity than using specific antibodies is not known at present.…”

Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival

“…Although none of the DC immune markers has perfect sensitivity or specificity, DC-SIGN, which participates in T cell stimulation, [14][15][16][17] is considered reliable in distinguishing myeloid DCs from macrophages. 18,19 In kidney biopsies, DC-SIGN + cells stain with other known kidney DC markers (BDCA-1, 8 HLA-DR, 8 CD68, 7,8 and CX3CR1 10 ), show an activated but not fully mature DC phenotype, and are associated with high T cell stimulation capability.…”

Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran

“…Targeting of dextran-binding receptors (e.g., MR and DC-SIGN) is a popular concept. In recent years studies devoted to the development of DC-SIGN therapeutic ligands have yielded new data in cell biology (203), immunology (204), and biochemistry (205, 206). The concept of therapeutic DC-SIGN antagonists/inhibitors is promising and in need of further development (9, 207).…”