Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver

Abstract

Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

“…Dendritic cells manipulation has also been proposed. Indeed, administration of HBV peptide-loaded DCs was reported to elicit functional HBV-specific CD8 cells and to reduce the viral load in Hepato-HuPBL mice (138) and a targeted antigen delivery to DCs was proven to efficiently induce local immunity to hepatotropic viruses in mice (139). Interestingly, in the context of cancer immunotherapy, PD-L1 silenced DCs were used for a DC vaccine that induced potent T cell responses (140).…”

GP96 and SMP30 Protein Priming of Dendritic Cell Vaccination Induces a More Potent CTL Response against Hepatoma

“…The literature also shows that HSP90 can stimulate DCs and induce CTL polarization and activation [ 16 ]. A study showed that cross-presenting DCs is highly effective in inducing CTLs capable of eliminating liver cancer [ 17 ].…”

Essential role of IκBNS for in vivo CD4+ T‐cell activation, proliferation, and Th1‐cell differentiation during Listeria monocytogenes infection in mice

“…Subsequently, cells were permeabilized (0.1% IGEPAL CA‐630 (Sigma‐Aldrich), 4 min, 4°C), washed and stained with anti‐IFN‐γ‐APC (XMG1.2), anti‐IL‐2‐PE (JES6‐5H4) or anti‐TNF‐α‐APC (MPC‐XT22) (BioLegend) for 30 min at 4°C. IκB NS ‐dependency of cytotoxic function in CD8 + T cells was determined as described before . Cells were analyzed with a BD FACS Canto II, BD LSR II (BD Biosciences) or an Attune NxT Acoustic Focusing Cytometer (Thermo Fisher Scientific).…”