Targeting Mycobacterium tuberculosis Antigens to Dendritic Cells via the DC-Specific-ICAM3-Grabbing-Nonintegrin Receptor Induces Strong T-Helper 1 Immune Responses

Abstract

Tuberculosis remains a major global health problem and efforts to develop a more effective vaccine have been unsuccessful so far. Targeting antigens (Ags) to dendritic cells (DCs) in vivo has emerged as a new promising vaccine strategy. In this approach, Ags are delivered directly to DCs via antibodies that bind to endocytic cell-surface receptors. Here, we explored DC-specific-ICAM3-grabbing-nonintegrin (DC-SIGN) targeting as a potential vaccine against tuberculosis. For this, we made use of the hSIGN mouse model that expresses human DC-SIGN under the control of the murine CD11c promoter. We show that in vitro and in vivo delivery of anti-DC-SIGN antibodies conjugated to Ag85B and peptide 25 of Ag85B in combination with anti-CD40, the fungal cell wall component zymosan, and the cholera toxin-derived fusion protein CTA1-DD induces strong Ag-specific CD4+ T-cell responses. Improved anti-mycobacterial immunity was accompanied by increased frequencies of Ag-specific IFN-γ+ IL-2+ TNF-α+ polyfunctional CD4+ T cells in vaccinated mice compared with controls. Taken together, in this study we provide the proof of concept that the human DC-SIGN receptor can be efficiently exploited for vaccine purposes to promote immunity against mycobacterial infections.

Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

“…It is this potency by DC-SIGN + cells to control adaptive immunity that has stimulated research that targets this receptor for therapeutic purposes. Indeed, recent progress has been made in using hDC-SIGN to target tumor-associated antigens to DCs for T cell activation ( 13 , 14 , 49 , 50 ). Indeed, in the hDC-SIGN:CD11c humanized mice, targeting OVA to hDC-SIGN on DCs elicited antigen-specific CD8 + T cell responses capable of eradicating OVA-expressing melanoma tumors ( 14 ).…”

“…Although eight DC-SIGN-related receptors are described in mice, the absence of a clear murine ortholog has hampered the in vivo validation of hDC-SIGN and has so far been performed with mice that express hDC-SIGN driven by the CD11c promoter ( 11 ). Subsequent targeting of antigens in this model has demonstrated the potency of hDC-SIGN on CD11c + DCs to internalize, process, and present antigen to T cells ( 12 , 13 ). For example, targeting of DC-SIGN in combination with genetic depletion of regulatory T cells was sufficient to induce long-term tumor regression in B16 melanoma-bearing mice ( 14 ).…”

Immune Response to Mycobacterium tuberculosis: A Narrative Review

“…The manipulation of the maturation of the DCs probably represents one of the winning strategies of Mbt that, by restraining the activity of DCs and, consequently, of T lymphocytes, allows the Mtb, whose speed of growth is relatively slow, to efficiently establish a bridgehead in the airways (35). Based on the above mentioned mechanism DC-SIGN has recently been proposed as a potential target for a vaccine purpose eventually able to enhance immunity against Mtb (36). On the other side, DC-SIGN may prevent tissue pathology by maintaining a balanced inflammatory state and thus promoting host protection (37).…”

Overexpression of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin in Dendritic Cells Protecting against Aspergillosis

“…DCs play an important role in immunity against aspergillosis and exert anti-aspergillus infection through multiple important signaling pathways. [ 8 ] Recent studies have shown that DC-SIGN was closely related to intracellular signaling in DCs after aspergillus infection. [ 7 ] In this study, the role of DC-SIGN in the processing of DC antigen presentation and T cells activation was investigated.…”

“…Dendritic cells (DCs) are the most powerful professional antigen-presenting cells, and responsible for antigen recognition and procession. [ 8 ] They could initiate primary immune response and play an important role in host defense against pathogen infection and tumor progression. The pattern recognition receptors on DCs recognize pathogen-associated molecular patterns.…”