Decreased Pathology and Prolonged Survival of Human DC-SIGN Transgenic Mice during Mycobacterial Infection

Abstract

Dendritic cell (DC)-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN: CD209) is a C-type lectin that binds ICAM-2,3 and various pathogens such as HIV, helicobacter, and mycobacteria. It has been suggested that Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, interacts with DC-SIGN to evade the immune system. To directly analyze the role of human DC-SIGN during mycobacterial infection, we generated conventional transgenic (tg) mice (termed "hSIGN") using CD209 cDNA under the control of the murine CD11c promoter. Upon mycobacterial infection, DCs from hSIGN mice produced significantly less IL-12p40 and no significant differences were be observed in the secretion levels of IL-10 relative to control DCs. After high dose aerosol infection with the strain M. tuberculosis H37Rv, hSIGN mice showed massive accumulation of DC-SIGN(+) cells in infected lungs, reduced tissue damage and prolonged survival. Based on our in vivo data, we propose that instead of favoring the immune evasion of mycobacteria, human DC-SIGN may have evolved as a pathogen receptor promoting protection by limiting tuberculosis-induced pathology.

Dendritic Cell-Specific ICAM-3–Grabbing Nonintegrin Expression on M2-Polarized and Tumor-Associated Macrophages Is Macrophage-CSF Dependent and Enhanced by Tumor-Derived IL-6 and IL-10

“…Therefore, M-CSF might drive the expression of DC-SIGN in tissue-resident macrophages in noninflamed tissues (homeostasis). Along this line, the ability of fibroblasts to modulate DC-SIGN expression on monocytes in an M-CSF-dependent manner (this manuscript), and the increased tissue repair and homeostasis observed in transgenic DC-SIGN mice after eradication of infectious agents (48), further support such a hypothesis.…”

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

“…21,37 hSIGN, hSIGNxDEREG mice, OT-I and OT-II tg were bred at the animal facilities of Twincore (Hannover, Germany) or VU University (Amsterdam, Netherlands) under specific pathogen-free conditions and used at 8-16 weeks of age. All experiments were performed according to institutional and national guidelines.…”

“…[17][18][19] As no functional homolog of DC-SIGN exists in mice, 20 we generated humanized mice expressing human DC-SIGN (hSIGN) on conventional DCs. 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.…”

HIV-1 Transmission by Dendritic Cell-specific ICAM-3-grabbing Nonintegrin (DC-SIGN) Is Regulated by Determinants in the Carbohydrate Recognition Domain That Are Absent in Liver/Lymph Node-SIGN (L-SIGN)

“…Genetic and epidemiological studies have also implicated a role for these lectins in vivo in response to pathogenic infection. Recent studies using DC-SIGN transgenic mice showed protection and prolonged survival of mycobacterial infection (27). In addition, genetic analysis revealed that individuals homozygous for specific polymorphisms in the L-SIGN repeat domain had a lower risk of severe acute respiratory syndrome coronavirus infection (28).…”