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

Lis Noelia Velasquez,Judith Bartel,Judith Bartel,Maria Virginia Gentilini,Maria Virginia Gentilini,Tim D Sparwasser,Tim D Sparwasser,Daniel Barkan,Hakan Kalay,Philipp Stüve,Philipp Stüve,Maxine Swallow,Maxine Swallow,Mariana Martina,Luciana Berod,Luciana Berod,Hugo D Lujan,Nils Yngve Lycke,Yvette Van Kooyk

doi:10.3389/fimmu.2018.00471

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.

Highlights

Tuberculosis (Tb) remains one of the leading causes of death worldwide with an estimated 10.4 million people becoming infected per year [1]
The capacity of antibodytargeted WT and hSIGN bone-marrow-derived dendritic cells (BMDCs) to promote T-cell responses was evaluated by co-culturing them with CellViolet-labeled CD4+ T cells purified from P25ktk mice, carrying a transgenic TCR that reacts to peptide 25 (P25) in the context of MHC class-II presentation [35]
We explored the potential of dendritic cells (DCs) targeting via human DC-SIGN as a novel vaccine strategy against Tb

Summary

Introduction

Tuberculosis (Tb) remains one of the leading causes of death worldwide with an estimated 10.4 million people becoming infected per year [1]. The only available vaccine against Tb is Mycobacterium bovis Bacillus Calmette-Guérin (BCG); it is only partially effective: it provides protection against severe forms of Tb in infants but is unable to prevent the development. Recent knowledge suggests that additional pathways could play important roles in vaccine-induced immunity against Tb. recent knowledge suggests that additional pathways could play important roles in vaccine-induced immunity against Tb In this respect, IL-23-driven Th17 cells were shown to contribute to the generation of antigen (Ag)-specific Th1 cells and the protection against Mycobacterium tuberculosis (Mtb) following vaccination with BCG [5] and proved to be key effector cells in different parenteral and mucosal subunit-based Tb vaccine models [6,7,8,9]. BCG- or environmental mycobacteria-induced regulatory T cells (Tregs) have been proposed as one of the reasons for the delayed onset of adaptive immunity observed in Tb and to limit the generation of sterilizing immunity [10, 11]

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